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Sample records for acid dota derivatives

  1. Biotin derivatives carrying two chelating DOTA units. Synthesis, in vitro evaluation of biotinidases resistance, avidin binding, and radiolabeling tests

    Pratesi, Alessandro; Bucelli, Francesca; Mori, Ilaria; Chinol, Marco; Verdoliva, Antonio; Paganelli, Giovanni; Rivieccio, Vincenzo; Gariboldi, Lucia; Ginanneschi, Mauro

    2010-01-01

    The synthesis of four biotin derivatives carrying two DOTA moieties for each ligand (BisDOTA set) is reported, for increasing radiation/dose ratio and improving efficiency in the pretargeted avidin-biotin radioimmunotherapy. The biotin-containing scaffold of two BisDOTA was similar to the mono-DOTA derivative previously described. Then the scaffold was elongated by trifunctionalized spacers of different length and conjugated with one of the COOH groups of two DOTA. Two others were prepared st...

  2. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

    We aimed at designing and developing a novel bombesin analogue, DOTA-PEG4-BN(7-14) (DOTA-PESIN), with the goal of labelling it with 67/68Ga and 177Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG4). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [GaIII/LuIII]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [67Ga/177Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [67Ga/177Lu]-DOTA-PESIN. [67Ga/177Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [68Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the 177Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with 68/67Ga and targeted radionuclide therapy with 177Lu. (orig.)

  3. H5dotasa (=(alphaRS)-alpha-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), an Asymmetrical Derivative of H4dota (=1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic Acid) Substituted at One Acetate Pendant Arm: 1H-NMR and Potentiometric Studies of the Ligand and Its Lanthanide(III) Complexes

    André, João P.; Brücher, Ernö; Kiraly, Robert; Carvalho, Rui A.; Mäcke, Helmut; Geraldes, Carlos F. G. C.

    2005-01-01

    The ligand H5dotasa (=(alphaRS)-alpha-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent at the C(alpha) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (alphaR) and (alphaS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to those of H4d...

  4. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours

    Zhang, Hanwen; Maecke, Helmut R. [University Hospital Basel, Division of Radiological Chemistry, Department of Radiology, Basel (Switzerland); Schuhmacher, Jochen; Eisenhut, Michael [German Cancer Research Centre, Department of Radiopharmaceutical Chemistry, Heidelberg (Germany); Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, P.O. Box 62, Berne (Switzerland); Wild, Damian [University Hospital, Clinic and Institute of Nuclear Medicine, Department of Radiology, Basel (Switzerland)

    2007-08-15

    We aimed at designing and developing a novel bombesin analogue, DOTA-PEG{sub 4}-BN(7-14) (DOTA-PESIN), with the goal of labelling it with {sup 67/68}Ga and {sup 177}Lu for diagnosis and radionuclide therapy of prostate and other human cancers overexpressing bombesin receptors. The 8-amino acid peptide bombesin (7-14) was coupled to the macrocyclic chelator DOTA via the spacer 15-amino-4,7,10,13-tetraoxapentadecanoic acid (PEG{sub 4}). The conjugate was complexed with Ga(III) and Lu(III) salts. The GRP receptor affinity and the bombesin receptor subtype profile were determined in human tumour specimens expressing the three bombesin receptor subtypes. Internalisation and efflux studies were performed with the human GRP receptor cell line PC-3. Xenografted nude mice were used for biodistribution. [Ga{sup III}/Lu{sup III}]-DOTA-PESIN showed good affinity to GRP and neuromedin B receptors but no affinity to BB3. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN internalised rapidly into PC-3 cells whereas the efflux from PC-3 cells was relatively slow. In vivo experiments showed a high and specific tumour uptake and good retention of [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN. [{sup 67}Ga/{sup 177}Lu]-DOTA-PESIN highly accumulated in GRP receptor-expressing mouse pancreas. The uptake specificity was demonstrated by blocking tumour uptake and pancreas uptake. Fast clearance was found from blood and all non-target organs except the kidneys. High tumour-to-normal tissue ratios were achieved, which increased with time. PET imaging with [{sup 68}Ga]-DOTA-PESIN was successful in visualising the tumour at 1 h post injection. Planar scintigraphic imaging showed that the {sup 177}Lu-labelled peptide remained in the tumour even 3 days post injection. The newly designed ligands have high potential with regard to PET and SPECT imaging with {sup 68/67}Ga and targeted radionuclide therapy with {sup 177}Lu. (orig.)

  5. Synthesis and Characterization of DOTA-(amide)4 Derivatives: Equilibrium and Kinetic Behavior of Their Lanthanide(III) Complexes

    Pasha, Azhar; Tircsó, Gyula; Benyó, Enikő Tircsóné; Brücher, Ernő; Sherry, A. Dean

    2007-01-01

    Lanthanide complexes of tetraamide derivatives of DOTA are of interest today because of their application as chemical exchange saturation transfer (CEST) agents for magnetic resonance imaging (MRI). The protonation constants of some simple tetraamide derivatives of DOTA and the stability constants of the complexes formed with some endogenous metal ions, namely Mg2+, Ca2+, Cu2+, Zn2+, and lanthanide(III) ions, have been studied. These complexes were found to be considerably less stable than th...

  6. Evaluation of maleimide derivative of DOTA for site-specific labeling of recombinant affibody molecules.

    Ahlgren, Sara; Orlova, Anna; Rosik, Daniel; Sandström, Mattias; Sjöberg, Anna; Baastrup, Barbro; Widmark, Olof; Fant, Gunilla; Feldwisch, Joachim; Tolmachev, Vladimir

    2008-01-01

    Affibody molecules are a new class of small (7 kDa) scaffold affinity proteins, which demonstrate promising properties as agents for in vivo radionuclide targeting. The Affibody scaffold is cysteine-free and therefore independent of disulfide bonds. Thus, a single thiol group can be engineered into the protein by introduction of one cysteine. Coupling of thiol-reactive bifunctional chelators can enable site-specific labeling of recombinantly produced Affibody molecules. In this study, the use of 1,4,7,10-tetraazacyclododecane-1,4,7-tris-acetic acid-10-maleimidoethylacetamide (MMA-DOTA) for 111 In-labeling of anti-HER2 Affibody molecules His 6-Z HER2:342-Cys and Z HER2:2395-Cys has been evaluated. The introduction of a cysteine residue did not affect the affinity of the proteins, which was 29 pM for His 6-Z HER2:342-Cys and 27 pM for Z HER2:2395-Cys, comparable with 22 pM for the parental Z HER2:342. MMA-DOTA was conjugated to DTT-reduced Affibody molecules with a coupling efficiency of 93% using a 1:1 molar ratio of chelator to protein. The conjugates were labeled with 111 In to a specific radioactivity of up to 7 GBq/mmol, with preserved binding for the target HER2. In vivo, the non-His-tagged variant 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys demonstrated appreciably lower liver uptake than its His-tag-containing counterpart. In mice bearing HER2-expressing LS174T xenografts, 111 In-[MMA-DOTA-Cys61]-Z HER2:2395-Cys showed specific and rapid tumor localization, and rapid clearance from blood and nonspecific compartments, leading to a tumor-to-blood-ratio of 18 +/- 8 already 1 h p.i. Four hours p.i., the tumor-to-blood ratio was 138 +/- 8. Xenografts were clearly visualized already 1 h p.i. PMID:18163536

  7. Complexation and biodistribution study of 111In complexes of bifunctional phosphinic acid analogues of H4DOTA

    Forsterová, Michaela; Zimová, Jana; Petrík, M.; Lázníček, M.; Lázníčková, A.; Hermann, P.; Melichar, František

    2007-01-01

    Roč. 2, č. 337 (2007), s. 34-34. ISSN 1619-7070 R&D Projects: GA AV ČR 1QS100480501 Institutional research plan: CEZ:AV0Z10480505 Keywords : bifunctional H4DOTA ligands * phosphinic acid analogues, * complexation of 111In Subject RIV: FR - Pharmacology ; Medidal Chemistry

  8. Mechanism and energetics for complexation of 90Y with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a model for cancer radioimmunotherapy

    A promising cancer therapy involves the use of the macrocyclic polyaminoacetate DOTA (1,4,6,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) attached to a tumor-targeting antibody complexed with the β emitter 90Y3+. However, incorporation of the 90Y into the DOTA conjugate is too slow. To identify the origins of this problem, ab initio quantum chemistry methods (B3LYP/:ACVP* and HF/LACVP*) were used to predict structures and energetics. The authors find that the initial complex YH2(DOTA)+ is 4-coordinate (the four equivalent carboxylate oxygens), which transforms to YH(DOTA) (5-coordinate with one ring N and four carboxylate oxygens), and finally to Y(DOTA)-, which is 8-coordinate (four oxygens and four nitrogens). The rate-determining step is the conversion of YH(DOTA) to Y(DOTA)-, which was calculated to have an activation free energy (aqueous phase) of 8.4 kcal/mol, in agreement with experimental results (8.1--9.3 kcal/mol) for various metals to DOTA [Kumar, K.; Tweedle, M.F. Inorg. Chem. 1993, 32, 4193--4199; Wu, S.L.; Horrocks, W.D., Jr., Inorg. Chem. 1995, 34, 3724--2732]. On the basis of this mechanism the authors propose a modified chelate, DO3AlPr, which has calculated at a much faster rate of incorporation

  9. DOTA-functionalized polylysine: a high number of DOTA chelates positively influences the biodistribution of enzymatic conjugated anti-tumor antibody chCE7agl.

    Jürgen Grünberg

    Full Text Available Site-specific enzymatic reactions with microbial transglutaminase (mTGase lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N'-N''-N'''-tetraacetic acid (DOTA chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA1-decalysine, (DOTA3-decalysine or (DOTA5-decalysine to the antibody heavy chain (via Gln295/297 gave rise to immunoconjugates containing two, six or ten DOTA moieties respectively. Radiolabeling of the immunoconjugates with (177Lu yielded specific activities of approximately 70 MBq/mg, 400 MBq/mg and 700 MBq/mg with increasing numbers of DOTA chelates. Biodistribution experiments in SKOV3ip human ovarian cancer cell xenografts demonstrated a high and specific accumulation of radioactivity at the tumor site for all antibody derivatives with a maximal tumor accumulation of 43.6±4.3% ID/g at 24 h for chCE7agl-[(DOTA-decalysine]2, 30.6±12.0% ID/g at 24 h for chCE7agl-[(DOTA3-decalysine]2 and 49.9±3.1% ID/g at 48 h for chCE7agl-[(DOTA5-decalysine]2. The rapid elimination from the blood of chCE7agl-[(DOTA-decalysine]2 (1.0±0.1% ID/g at 24 h is associated with a high liver accumulation (23.2±4.6% ID/g at 24 h. This behavior changed depending on the numbers of DOTA moieties coupled to the decalysine peptide with a slower blood clearance (5.1±1.0 (DOTA3 versus 11.7±1.4% ID/g (DOTA5, p<0.005 at 24 h and lower radioactivity levels in the liver (21.4±3.4 (DOTA3 versus 5.8±0.7 (DOTA5, p<0.005 at 24 h. We conclude that the site-specific and stoichiometric uniform conjugation of the highly DOTA-substituted decalysine ((DOTA5-decalysine to an anti-tumor antibody leads to the formation of immunoconjugates with high specific activity and excellent in vivo behavior and is a valuable option for

  10. DOTASA, an Asymmetrical Derivative of DOTA Substituted at one Acetate pendant Arm: 1H NMR and Potentiometric Studies of the Ligand and its Lanthanide(III) Complexes

    André, João P.; Brücher, Ernö; Kiraly, Robert; Carvalho, Rui A.; Mäcke, Helmut; Geraldes, Carlos F. G. C.

    2005-01-01

    The ligand H5dotasa (=(alphaRS)-alpha-(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) is a H4dota-like macrocyclic ligand with a carboxymethyl CH2COOH substituent moiety at the C(alpha) atom of one of the four acetate pendant arms of H4dota (=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), present as a racemic mixture of (alphaR) and (alphaS) enantiomers. The protonation constants of the ligand were determined by potentiometry, giving values close to H4dot...

  11. Influence of physico-chemical parameters on the optimization of the radiolabeling of DOTA-based phosphonic acids with 44Sc

    Full text of publication follows. 44Sc as a positron emitter can be an interesting alternative to 68Ga (t1/2=67.71 min) due to its longer half-life (t1/2=3.97 h). It has been already proposed as a PET radionuclide for studying bone disease and is already available as a 44Ti/44Sc generator. 44Sc has an isomeric state, 44mSc (t1/2=58.6 h), which is co-produced with 44Sc and that is expected to be used as an in vivo PET generator 44mSc/44Sc. It would thus allow to monitor the kinetics over long periods of time.The 44Sc is a trivalent metal cation and should be suitable for complexation with chelators alone or with bifunctional ligands conjugated to peptides or other molecular targeting vectors. The DOTA macro cyclics ligand form stable complexes with many cations besides scandium. The aim of this work was to evaluate the phosphonic acid DOTA derivatives, new ligands which can be applied for labeling biomolecules with Scandium radionuclides. Potentiometric studies showed that the ligands have a similar basicity to the parent H4dota and the stability constants of their complexes with Sodium (I) and selected lanthanide (III) ions are also similar. It was found that the phosphonic acid derivatives formed complexes relatively fast [Ref.1]. It is also known that the phosphorus acid derivatives and their complexes have some different properties (size and shape of the coordinating group, overall hydrophilicity or acidity/basicity of the ligands) if compared to their acetate analogs [Ref.2], [Ref.3]. It was proved that the mono-phosphorus acid analogs of H4dota form thermodynamically very stable and kinetically inert complexes with Ce3+ and Gd3+ [Ref.4] as well as Y3+ [Ref.5]. The influence of various reaction parameters and conditions on radiolabelling efficiency, such as the amount of ligand, pH range, reaction time and reaction temperature, were investigated and optimized in order to maximize the radiochemical yield. Comparison between the results obtained with 44Ti/44Sc

  12. Evaluation of 111In-labeled macrocyclic chelator-amino acid derivatives for cancer imaging

    Purpose: We evaluated new 111In-labeled amino acid derivatives, in which the amino acids are conjugated with1,4,7,10-tetra-azacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7,10-tetraazacyclododecane-1,7-diacetic acid (DO2A) or 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A). Methods: DOTA-aminoalanine (DOTA-A), DOTA-aminohomoalanine (DOTA-H), DOTA-lysine (DOTA-L), DO2A-alanine (DO2A-A), DO3A-alanine (DO3A-A) and DO3A-homoalanine (DO3A-H) were labeled with 111In. In vitro cell uptake assays were performed usingHep3B (a human hepatoma cell line), CT26 (a mouse colon cancer cell line) and U87MG (a human glioma cell line). In vitro cell uptake inhibition assays were performed using U87MG and 111In-DO3A-H. U87MG bearing xenografted mice were subject to biodistribution, SPECT imaging, autoradiography, and immunohistochemistry studies. Results: Of the amino acid derivatives and cell lines examined, U87MG and 111In-DO3A-H showed highest uptake in vitro. This uptake was blocked by 2-aminobicyclo-[2,2,1] heptane-2-carboxylic acid (BCH) and by tryptophan. 111In-DO3A-HSPECT imaging of U87MG bearing xenografted mice visualized tumors (mean tumor-to-muscle ratio 3.16±0.74). Autoradiography and immunohistochemistry revealed that 111In-DO3A-H uptake matched L-type amino acid transporter 1 expression. Conclusion: Tumor uptake was successfully imaged using 111In-DO3A-H in U87MG bearing xenografted mice. 111In-DO3A-H appears to be useful for imaging tumors expressing L-type amino acid transporter.

  13. Scandium(iii) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with (44)Sc from cyclotron and from a (44)Ti/(44)Sc generator.

    Kerdjoudj, R; Pniok, M; Alliot, C; Kubíček, V; Havlíčková, J; Rösch, F; Hermann, P; Huclier-Markai, S

    2016-01-19

    The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine. PMID:26675416

  14. Influence of biological assay conditions on stability assessment of radiometal-labelled peptides exemplified using a {sup 177}Lu-DOTA-minigastrin derivative

    Ocak, Meltem [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria); Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul University, 34116, Istanbul (Turkey); Helbok, Anna; Guggenberg, Elisabeth von [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria); Ozsoy, Y. [Department of Pharmaceutical Technology, Pharmacy Faculty, Istanbul University, 34116, Istanbul (Turkey); Kabasakal, Levent [Department of Nuclear Medicine, Cerrahpasa Medical Faculty, 34098, Istanbul (Turkey); Kremser, Leopold [Division of Clinical Biochemistry, Protein Micro-Analysis Facility, Biocenter, Medical University Innsbruck, A-6020, Innsbruck (Austria); Decristoforo, Clemens, E-mail: clemens.decristoforo@uki.a [Clinical Department of Nuclear Medicine, Medical University Innsbruck, A-6020, Innsbruck (Austria)

    2011-02-15

    Introduction: Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. Methods: In vitro stability of a DOTA-minigastrin derivative ({sup 177}Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH{sub 2}) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. Results: Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. Conclusion: Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations.

  15. Influence of biological assay conditions on stability assessment of radiometal-labelled peptides exemplified using a 177Lu-DOTA-minigastrin derivative

    Introduction: Lack of correlation between in vitro and in vivo stability is a general problem for the development of radiopeptides especially in the case of minigastrin derivatives for therapeutic applications. In this study, we compared the influence of experimental conditions on radiopeptide stability results in vitro using a model Minigastrin (MG) analogue labelled with Lu-177. Additionally, we attempted to characterize the main serum enzymatic cleavage sites by matrix-assisted laser desorption/ionization (MALDI) time-of-flight (TOF) mass spectrometry (MS) analysis. Methods: In vitro stability of a DOTA-minigastrin derivative (177Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-NIe-Asp-Phe-NH2) was tested in serum, rat tissue homogenates and two different standardised enzymatic mixtures. Quantification of the metabolised radiopeptides at different time intervals was performed using reversed-phase high-performance liquid chromatography (RP-HPLC). Metabolites were characterised by MALDI-TOF-MS. Urine was collected after 15 min p.i. into the mice and compared with in vitro metabolites by RP-HPLC. Results: Faster degradation of the radiopeptide was found in blood in comparison with plasma and serum incubation and in components from rats faster than from human origin. Fast degradation was observed in kidney and liver homogenates as well as in standardised enzymatic mixtures, also revealing variations in the metabolic profile. In urine, no intact peptide was detected already 5 min post injection. MALDI-TOF-MS revealed major cleavage sites at the carboxy terminus of the peptide. Conclusion: Very variable results may be found when different kind of incubation media for testing radiopeptide stabilities is used. Serum incubation studies may overestimate stability; therefore, results should be interpreted with care and combined with alternative in vitro and in vivo investigations.

  16. Associating a negatively charged GdDOTA-derivative to the Pittsburgh compound B for targeting Aβ amyloid aggregates.

    Martins, André F; Oliveira, Alexandre C; Morfin, Jean-François; Laurents, Douglas V; Tóth, Éva; Geraldes, Carlos F G C

    2016-03-01

    We have conjugated the tetraazacyclododecane-tetraacetate (DOTA) chelator to Pittsburgh compound B (PiB) forming negatively charged lanthanide complexes, Ln(L4), with targeting capabilities towards aggregated amyloid peptides. The amphiphilic Gd(L4) chelate undergoes micellar aggregation in aqueous solution, with a critical micellar concentration of 0.68 mM, lower than those for the neutral complexes of similar structure. A variable temperature (17)O NMR and NMRD study allowed the assessment of the water exchange rate, k ex (298) = 9.7 × 10(6) s(-1), about the double of GdDOTA, and for the description of the rotational dynamics for both the monomeric and the micellar forms of Gd(L4). With respect to the analogous neutral complexes, the negative charge induces a significant rigidity of the micelles formed, which is reflected by slower and more restricted local motion of the Gd(3+) centers as evidenced by higher relaxivities at 20-60 MHz. Surface Plasmon Resonance results indicate that the charge does not affect significantly the binding strength to Aβ1-40 [K d = 194 ± 11 μM for La(L4)], but it does enhance the affinity constant to human serum albumin [K a = 6530 ± 68 M(-1) for Gd(L4)], as compared to neutral counterparts. Protein-based NMR points to interaction of Gd(L4) with Aβ1-40 in the monomer state as well, in contrast to neutral complexes interacting only with the aggregated form. Circular dichroism spectroscopy monitored time- and temperature-dependent changes of the Aβ1-40 secondary structure, indicating that Gd(L4) stabilizes the random coil relative to the α-helix and β-sheet. TEM images confirm that the Gd(L4) complex reduces the formation of aggregated fibrils. PMID:26613605

  17. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with 68Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    Highlights: •PET images showed high uptake of 68Ga-DOTA-octreotide in the normal pancreas. •68Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of 68Ga-DOTA-octreotide was decreased in the diabetic rats. •68Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with 68Gallium (68Ga). After intravenous injection of 68Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that 68Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of 68Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with 68Ga-DOTA-octreotide could be a potential tool for evaluating BCM

  18. The chemical fate of 212Bi-DOTA formed by β- decay of 212Pb(DOTA)2-

    The increasing use of inert metal complexes in radioimmunotherapy prompted us to explore the potential use of 212Pb chelates. Herein, we report a study of the chemical fate of the 212Bi-DOTA complex formed by β- decay of 212Pb(DOTA)2-(H4DOTA = 1,4,7,10-tetraazacyclododecanetetraacetic acid). To assure that both parent and daughter complexes were thermally stable, kinetic studies were performed with 203Pb(II) and 206Bi(III) which showed that both lead and bismuth complexes with DOTA undergo chemical exchange only very slowly in aqueous solution at pH 4-10. To investigate whether the complex ion which results from decay of 212Pb(DOTA)2- was intact and also stable, solutions initially containing only this ion were analyzed for amounts of DOTA-complexed and uncomplexed 212Bi after attaining transient equilibrium with 212Bi. The fraction of 212Bi radioactivity not complexed to DOTA, vide infra, was found to be 36±2%. This value represents the fraction of breakup of 212Bi(DOTA)- formed from β- decay of the parent complex. By considering the various extranuclear processes responsible for kinetic and electronic excitation of the 212Bi daughter, break-up of the 212Bi-DOTA complex is ascribed to the internal conversion of γ-rays emitted by the excited 212Bi nuclide. (orig.)

  19. DOTA-Tyr3-octreotate labelled with 177Lu and 131I. A comparative evaluation

    The chemical structure of somatostatin receptor ligand 1,4,7,10-tetraazacyclododecane- N,N',N',N'''-tetraacetic acid-Tyr3-octreotate (DOTA-Tyr3-TATE), provides the means for radiolabelling with halogen, by electrophilic substitution, to the Tyr3 residue and with metal, by a coordination mechanism, to the DOTA chelator. In this study, the DOTA-Tyr3-TATE was radiolabelled with 177Lu and 131I of high radiochemical purity and specific activity. The in vitro study regarding the competitive and the saturation binding assays were performed using rat brain cortex membrane. The IC50 value was determined as 4.74nM for natLu-DOTA-Tyr3-TATE and the Kd value was 142.8pM for 177Lu-DOTA-Tyr3-TATE. The biodistribution data of 177Lu-DOTA-Tyr3-TATE and DOTA-131I-Tyr3-TATE in HRS1 (hepato-colangiom carcinomas) tumour bearing rats, show that the 177Lu-DOTA-Tyr3-TATE is more stable and has better uptake than DOTA-131I-Tyr3-TATE. Furthermore, the competitive localization index of 177Lu- DOTA-Tyr3-TATE is three times higher than that obtained for DOTA-131I -Tyr3-TATE. The results of work based on comparative experiments suggest that 177Lu-DOTA-Tyr3- TATE could be an effective targeted radiotherapy agent of SSTR tumours. (author)

  20. Joint analysis of ESR lineshapes and 1H NMRD profiles of DOTA-Gd derivatives by means of the slow motion theory

    Kruk, D.; Kowalewski, J.; Tipikin, D. S.; Freed, J. H.; Mościcki, M.; Mielczarek, A.; Port, M.

    2011-01-01

    The "Swedish slow motion theory" [Nilsson and Kowalewski, J. Magn. Reson. 146, 345 (2000)] applied so far to Nuclear Magnetic Relaxation Dispersion (NMRD) profiles for solutions of transition metal ion complexes has been extended to ESR spectral analysis, including in addition g-tensor anisotropy effects. The extended theory has been applied to interpret in a consistent way (within one set of parameters) NMRD profiles and ESR spectra at 95 and 237 GHz for two Gd(III) complexes denoted as P760 and P792 (hydrophilic derivatives of DOTA-Gd, with molecular masses of 5.6 and 6.5 kDa, respectively). The goal is to verify the applicability of the commonly used pseudorotational model of the transient zero field splitting (ZFS). According to this model the transient ZFS is described by a tensor of a constant amplitude, defined in its own principal axes system, which changes its orientation with respect to the laboratory frame according to the isotropic diffusion equation with a characteristic time constant (correlation time) reflecting the time scale of the distortional motion. This unified interpretation of the ESR and NMRD leads to reasonable agreement with the experimental data, indicating that the pseudorotational model indeed captures the essential features of the electron spin dynamics.

  1. Y-90-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    The goal of this work was to determine an optimal radioimmunotherapy agent for non-Hodgkin's lymphoma. We established the stability profile of yttrium-90-labeled humanized LL2 (hLL2) monoclonal antibody prepared with different chelating agents, and from these data estimated the improvement using the most stable yttrium-90 chelate-hLL2 complex. Methods: The complementary-determining region- (cdr)-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to derivatives of DTPA and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). The conjugates were labeled with Y-90 and tested against a 10,000-fold molar excess of free DTPA and against human serum. The conjugates were also labeled with Y-88 and compared for biodistribution in normal and lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each. Results: Y-90-DOTA -mAb were stable to either DTPA or serum challenge. DTPA complexes of hLL2 lost 3-4% of Y-90 (days 1-4) and 10-15% thereafter. In vivo, stability differences showed lower Y-90 uptake in bone using DOTA. Absorbed doses per 37 MBq (1 mCi) Y-90-mAb were 3555 and 5405 cGy for bone, and 2664 and 4524 cGy for washed-bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52% and 69.8% increases in absorbed radiation doses for bone and washed-bone when switching from a DOTA to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents a preferred agent for RAIT of non-Hodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, as compared to yttrium-90-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this will result in a substantial toxicological advantage for a DOTA-based hLL2 conjugate

  2. Preliminary Therapy Evaluation of 225Ac-DOTA-c(RGDyK) Demonstrates that Cerenkov Radiation Derived from 225Ac Daughter Decay Can Be Detected by Optical Imaging for In Vivo Tumor Visualization

    Pandya, Darpan N.; Hantgan, Roy; Budzevich, Mikalai M.; Kock, Nancy D.; Morse, David L.; Batista, Izadora; Mintz, Akiva; Li, King C.; Wadas, Thaddeus J.

    2016-01-01

    The theranostic potential of 225Ac-based radiopharmaceuticals continues to increase as researchers seek innovative ways to harness the nuclear decay of this radioisotope for therapeutic and imaging applications. This communication describes the evaluation of 225Ac-DOTA-c(RGDyK) in both biodistribution and Cerenkov luminescence imaging (CLI) studies. Initially, La-DOTA-c(RGDyK) was prepared as a non-radioactive surrogate to evaluate methodologies that would contribute to an optimized radiochemical synthetic strategy and estimate the radioactive conjugate's affinity for αvβ3, using surface plasmon resonance spectroscopy. Surface plasmon resonance spectroscopy studies revealed the IC50 and Ki of La-DOTA-c(RGDyK) to be 33 ± 13 nM and 26 ± 11 nM, respectively, and suggest that the complexation of the La3+ ion to the conjugate did not significantly alter integrin binding. Furthermore, use of this surrogate allowed optimization of radiochemical synthesis strategies to prepare 225Ac-DOTA-c(RGDyK) with high radiochemical purity and specific activity similar to other 225Ac-based radiopharmaceuticals. This radiopharmaceutical was highly stable in vitro. In vivo biodistribution studies confirmed the radiotracer's ability to target αvβ3 integrin with specificity; specificity was detected in tumor-bearing animals using Cerenkov luminescence imaging. Furthermore, tumor growth control was achieved using non-toxic doses of the radiopharmaceutical in U87mg tumor-bearing nude mice. To our knowledge, this is the first report to describe the CLI of αvβ3+ tumors in live animals using the daughter products derived from 225Ac decay in situ. This concept holds promise to further enhance development of targeted alpha particle therapy. PMID:27022417

  3. Positron emission tomography study on pancreatic somatostatin receptors in normal and diabetic rats with {sup 68}Ga-DOTA-octreotide: A potential PET tracer for beta cell mass measurement

    Sako, Takeo [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Hasegawa, Koki; Nishimura, Mie; Kanayama, Yousuke; Wada, Yasuhiro; Hayashinaka, Emi; Cui, Yilong; Kataoka, Yosky [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Senda, Michio [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Division of Molecular Imaging, Institute of Biomedical Research and Innovation, 2-2 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan); Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Watanabe, Yasuyoshi, E-mail: yywata@riken.jp [Division of Bio-function Dynamics Imaging, RIKEN Center for Life Science Technologies, 6-7-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-0047 (Japan)

    2013-12-06

    Highlights: •PET images showed high uptake of {sup 68}Ga-DOTA-octreotide in the normal pancreas. •{sup 68}Ga-DOTA-octreotide specifically binds to somatostatin receptors in the pancreas. •The pancreatic uptake of {sup 68}Ga-DOTA-octreotide was decreased in the diabetic rats. •{sup 68}Ga-DOTA-octreotide could be a candidate PET probe to measure the beta cell mass. -- Abstract: Diabetes mellitus (DM) is a metabolic disorder characterized by hyperglycemia, and the loss or dysfunction of pancreatic beta cells has been reported before the appearance of clinical symptoms and hyperglycemia. To evaluate beta cell mass (BCM) for improving the detection and treatment of DM at earlier stages, we focused on somatostatin receptors that are highly expressed in the pancreatic beta cells, and developed a positron emission tomography (PET) probe derived from octreotide, a metabolically stable somatostatin analog. Octreotide was conjugated with 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a chelating agent, and labeled with {sup 68}Gallium ({sup 68}Ga). After intravenous injection of {sup 68}Ga-DOTA-octreotide, a 90-min emission scan of the abdomen was performed in normal and DM model rats. The PET studies showed that {sup 68}Ga-DOTA-octreotide radioactivity was highly accumulated in the pancreas of normal rats and that the pancreatic accumulation was significantly reduced in the rats administered with an excess amount of unlabeled octreotide or after treatment with streptozotocin, which was used for the chemical induction of DM in rats. These results were in good agreement with the ex vivo biodistribution data. These results indicated that the pancreatic accumulation of {sup 68}Ga-DOTA-octreotide represented specific binding to the somatostatin receptors and reflected BCM. Therefore, PET imaging with {sup 68}Ga-DOTA-octreotide could be a potential tool for evaluating BCM.

  4. Radiolabeled derivatives of folic acid

    Derivatives of folic acid are described, in which the α-carboxyl group is substituted with an amino compound having an aromatic or heterocyclic ring substituent which is capable of being radiolabelled. Particularly mentioned as a radiolabel is 125I. (author)

  5. Comparative study on DOTA-derivatized bombesin analog labeled with 90Y and 177Lu: in vitro and in vivo evaluation

    Introduction: The aim of the study was to compare in vitro and in vivo a novel DOTA-chelated bombesin (BN) analog of the amino acid sequence, QRLGNQWAVGHLM-CONH2 (BN[2-14]NH2), labeled with 90Y and 177Lu, for its potential use in targeted radiotherapy of tumors expressing gastrin releasing peptide (GRP) receptors. The same amino acid sequence, but with different chelator, referred as BN1.1 (Gly-Gly-Cys-Aca-QRLGNQWAVGHLM-CONH2), has already been studied and reported; however, the DOTA-chelated one, suitable for labeling with M+3 type radiometals, was not yet described. Methods: The conditions for labeling of DOTA-BN[2-14]NH2 with noncarrier added 90Y and with 177Lu [specific activity (SA), 15 Ci/mg Lu] were investigated and optimized to provide 90Y-DOTA-BN[2-14]NH2 and 177Lu-DOTA-BN[2-14]NH2 of high SA. The stability of the radiolabeled compounds in human serum was evaluated over a period of 24 h. The human prostate cancer cell line PC-3, known to express GRP receptors, was used for in vitro evaluation of radiolabeled peptide affinity to GRP receptors and for assessment of cytotoxicity of both nonlabeled and radiolabeled peptide. Biodistribution accompanied by receptor blocking was studied in normal Swiss mice. Results: 90Y-DOTA-BN[2-14]NH2 and 177Lu-DOTA-BN[2-14]NH2 were obtained with radiochemical yield >98% and high SA (67.3 GBq 90Y/μmol and 33.6 GBq 177Lu/μmol, respectively). They were stable when incubated in human serum for up to 24 h. The binding affinities of DOTA-BN[2-14]NH2 and both natY- and natLu-labeled analogs to GRP receptors were high (IC50=1.78, 1.99, and 1.34 nM, respectively), especially for the natLu-DOTA-BN[2-14]NH2 complex. The cytotoxicity study of DOTA-BN[2-14]NH2 to PC-3 cells revealed an IC50=6300 nM after 72 h of exposition, while the labeled derivatives showed no significant cytotoxic effect. The internalization rate to PC-3 cells was more rapid for 177Lu-labeled peptide (84.87%) than for the 90Y-labeled one (80.79%), while the efflux

  6. Reducing Renal Uptake of {sup 177}Lu Labeled CCK Derivative using Basic Amino Acids

    Lee, Soyoung; Lim, Jaecheong; Joh, Eunha [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    Radiolabeled peptides have been designed to target the relative receptors overespressed in tumor cells, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), glucagon-like peptide-a receptor (GLP-1R), and cholecystokinin (CCK) receptor. Most of these peptides are eliminated from the body via the kidney and are partly reabsorbed in the proximal tubular cells. However, the high renal uptake of the radiolabeled peptides may lead to renal toxicity. In this study we investigated various amino acid solutions to reduce the renal uptake of {sup 177}Lu-DOTA-CCK derivative. Renal uptake of {sup 177}Lu-DOTA-CCK derivative is effectively reduced by the administration of positively charged amino acids. The administration of 12 mg of L-lysine was as effective in reducing the renal uptake as 6 mg of lysine and 6 mg of arginine combinations. Further studies will be performed to identify the most potent inhibitor of renal reuptake of radiolabeled peptides and minimize the chance of unwanted side effects.

  7. Reducing Renal Uptake of 177Lu Labeled CCK Derivative using Basic Amino Acids

    Radiolabeled peptides have been designed to target the relative receptors overespressed in tumor cells, such as integrin αvβ3, gastrin-releasing peptide receptor (GRPR), melanocortin-1 receptor (MC1-R), glucagon-like peptide-a receptor (GLP-1R), and cholecystokinin (CCK) receptor. Most of these peptides are eliminated from the body via the kidney and are partly reabsorbed in the proximal tubular cells. However, the high renal uptake of the radiolabeled peptides may lead to renal toxicity. In this study we investigated various amino acid solutions to reduce the renal uptake of 177Lu-DOTA-CCK derivative. Renal uptake of 177Lu-DOTA-CCK derivative is effectively reduced by the administration of positively charged amino acids. The administration of 12 mg of L-lysine was as effective in reducing the renal uptake as 6 mg of lysine and 6 mg of arginine combinations. Further studies will be performed to identify the most potent inhibitor of renal reuptake of radiolabeled peptides and minimize the chance of unwanted side effects

  8. Molecular Evolution of the dotA Gene in Legionella pneumophila

    Ko, Kwan Soo; Hong, Seong Karp; Lee, Hae Kyung; Park, Mi-Yeoun; Kook, Yoon-Hoh

    2003-01-01

    The molecular evolution of dotA, which is related to the virulence of Legionella pneumophila, was investigated by comparing the sequences of 15 reference strains (serogroups 1 to 15). It was found that dotA has a complex mosaic structure. The whole dotA gene of Legionella pneumophila subsp. pneumophila serogroups 2, 6, and 12 has been transferred from Legionella pneumophila subsp. fraseri. A discrepancy was found between the trees inferred from the nucleotide and deduced amino acid sequences ...

  9. Identification, characterization and suppression of side-products formed during the synthesis of high dose 68Ga-DOTA-TATE

    In the course of the establishment of 68Ga-DOTA-TATE production for clinical use a shoulder comprising presumably several impurities was observed in the chromatogram of the analytical radio-HPLC. LC–MS/MS results support the hypothesis that some of these radioimpurities are radiolytic oxidation by-products of 68Ga-DOTA-TATE. A new HPLC method was developed for quality control of 68Ga-DOTA-TATE. Significant improvement on the radiochemical purity of 68Ga-DOTA-TATE was achieved by the addition of ascorbic acid or ethanol to the reaction mixture. - Highlights: ► A new HPLC method was developed for quality control of 68Ga-DOTA-TATE. ► Radiolytic oxidation by-products of 68Ga-DOTA-TATE were formed at high dose of activity. ► It is necessary to add ascorbic acid or ethanol to the preparation for high dose of 68Ga-DOTA-TATE

  10. Y-90-DOTA-hLL2: An Agent for Radioimmunotherapy of Non-Hodgkin's Lymphoma

    Griffiths, Gary L.(Immunomedics, Inc.); Govindan, Serengulam V.(Immunomedics, Inc.); Sharkey, Robert M.(Immunomedics, Inc.); Fisher, Darrell R.(BATTELLE (PACIFIC NW LAB)); Goldenberg, David M.(Immunomedics, Inc.)

    2003-01-01

    The goal of this work was to determine an optimal radioimmunotherapy agent for non-Hodgkin's lymphoma. We established the stability profile of yttrium-90-labeled humanized LL2 (hLL2) monoclonal antibody prepared with different chelating agents, and from these data estimated the improvement using the most stable yttrium-90 chelate-hLL2 complex. Methods: The complementary-determining region- (cdr)-grafted (humanized) anti-CD22 mAb, hLL2 (epratuzumab), was conjugated to derivatives of DTPA and 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA). The conjugates were labeled with Y-90 and tested against a 10,000-fold molar excess of free DTPA and against human serum. The conjugates were also labeled with Y-88 and compared for biodistribution in normal and lymphoma xenograft-bearing athymic mice. In vivo data were analyzed for uptake of yttrium in bone and washed bone when either the DOTA or the Mx-DTPA chelates were used, and dosimetry calculations were made for each. Results: Y-90-DOTA -mAb were stable to either DTPA or serum challenge. DTPA complexes of hLL2 lost 3-4% of Y-90 (days 1-4) and 10-15% thereafter. In vivo, stability differences showed lower Y-90 uptake in bone using DOTA. Absorbed doses per 37 MBq (1 mCi) Y-90-mAb were 3555 and 5405 cGy for bone, and 2664 and 4524 cGy for washed-bone for 90Y-DOTA-hLL2 and 90Y-MxDTPA-hLL2, respectively, amounting to 52% and 69.8% increases in absorbed radiation doses for bone and washed-bone when switching from a DOTA to a Mx-DTPA chelate. Conclusion: Y-90-hLL2 prepared with the DOTA chelate represents a preferred agent for RAIT of non-Hodgkin's lymphoma, with an in vivo model demonstrating a large reduction in bone-deposited yttrium, as compared to yttrium-90-hLL2 agents prepared with open-chain DTPA-type chelating agents. Dosimetry suggests that this will result in a substantial toxicological advantage for a DOTA-based hLL2 conjugate.

  11. TmDOTA -: A Sensitive Probe for MR Thermometry in Vivo

    Zuo, Chun S.; Mahmood, Ashfaq; Sherry, A. Dean

    2001-07-01

    The lanthanide complex, thulium 1,4,7,10-tetraazacyclodo- decane-1,4,7,10-tetraacetic acid (TmDOTA-), has been investigated as an agent for MR thermometry in vivo. The chemical shifts of the TmDOTA- protons were highly sensitive to temperature at a clinically relevant field strength, yet insensitive to pH and the presence of Ca2+. Given the excellent stability of lanthanide-DOTA complexes and high thermal sensitivity, TmDOTA- is expected to be a good candidate for MR thermometry in vivo.

  12. Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

    Kunikazu Moribe; Waree Limwikrant; Kenjirou Higashi; Keiji Yamamoto

    2011-01-01

    Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs...

  13. Yttrium-90 Radiolabelling of Biotin DOTA

    Yttrium-90 1,4,7,10-tetraazacyclododecane 1,4,7,10-tetraacetic acid (DOTA) biotin was prepared by adding an equal volume of sodium acetate (1.0M, pH5.0) to the 90YCl3 vial (concentration 37–74 GBq/mL in 0.05M HCl) containing 2.96–4.44 GBq of 90Y followed by 1.0 mg of biotin DOTA dissolved in 0.5 mL of saline (recommended specific activity of 3.7 GBq/mg). After mixing, the reaction vial was incubated for 30 min at 95°C. Aliquots of the mixture were drawn at defined time intervals to determine the radiochemical purity (RCP)

  14. Preparation of DOTA-TATE and DOTA-NOC freeze-dried kits for formulation of patient doses of 177Lu-labeled agents and their comparison for peptide receptor radionuclide therapy application

    The objective of the present work is to prepare freeze-dried DOTA-TATE and DOTA-NOC kits for the easy and convenient preparation of patient doses of 177Lu-DOTA-TATE and 177Lu-DOTA-NOC, respectively at the hospital radiopharmacy and to compare the radio-peptides with respect to their radiochemical and biological behaviors. Freeze-dried kits of DOTA-TATE and DOTA-NOC, comprising a lyophilized mixture of 200 μg of DOTA-peptide, 80 mg of gentisic acid and 13.9 mg of ammonium acetate were prepared. Therapeutic doses of 177Lu-labeled peptides (up to 200 mCi, 7.4 GBq) were prepared using these kits and 177Lu, produced in-house, with >99 % radiochemical purity and high stability following an easy and convenient protocol. Comparative pharmacokinetic behavior of the radio-peptides was studied by carrying out biodistribution studies in normal Wistar rats which revealed higher retention of activity in several major organs and slower renal clearance for 177Lu-DOTA-NOC compared to that of 177Lu-DOTA-TATE. Preliminary pharmacokinetic studies, carried out in limited number of patients suffering from cancers of neuroendocrine origins, showed lower accumulation of activity in vital organs and faster renal clearance of 177Lu-DOTA-TATE compared to that of 177Lu-DOTA-NOC. (author)

  15. Caffeic acid derivatives from Bupleurum chinense

    Haghi, G.; Hatami, A.; Mehran, M.; Hosseini, H

    2014-01-01

    In this study, caffeic acid (CA) and its three derivatives including 3-caffeoylquinic acid (3-CQA, neochlorogenic acid), 4-caffeoylquinic acid (4-CQA, cryptochlorogenic acid), and 5-caffeoylquinic acid (5-CQA, chlorogenic acid) were identified in Bupleurum chinense aerial parts using reverse-phase high-performance liquid chromatography (RP-HPLC) with photodiode array (PDA) detector, reference compounds and chemical reactions. Separation was performed on a C18 column using gradient elution wit...

  16. Drug Nanoparticle Formulation Using Ascorbic Acid Derivatives

    Kunikazu Moribe

    2011-01-01

    Full Text Available Drug nanoparticle formulation using ascorbic acid derivatives and its therapeutic uses have recently been introduced. Hydrophilic ascorbic acid derivatives such as ascorbyl glycoside have been used not only as antioxidants but also as food and pharmaceutical excipients. In addition to drug solubilization, drug nanoparticle formation was observed using ascorbyl glycoside. Hydrophobic ascorbic acid derivatives such as ascorbyl mono- and di-n-alkyl fatty acid derivatives are used either as drugs or carrier components. Ascorbyl n-alkyl fatty acid derivatives have been formulated as antioxidants or anticancer drugs for nanoparticle formulations such as micelles, microemulsions, and liposomes. ASC-P vesicles called aspasomes are submicron-sized particles that can encapsulate hydrophilic drugs. Several transdermal and injectable formulations of ascorbyl n-alkyl fatty acid derivatives were used, including ascorbyl palmitate.

  17. Biological activities of substituted trichostatic acid derivatives

    Cédric Charrier; Joëlle Roche; Jean-Pierre Gesson; Philippe Bertrand

    2009-07-01

    New substituted trichostatic acid derivatives have been synthesized and evaluated for their biological activities towards the H661 non-small lung cancer cell line. These syntheses were achieved by alkylation of propiophenones to introduce the side chain with a terminal precursor of hydroxamic acid and aminobenzamide derivatives. The first fluorinated derivatives of trichostatic acid are described, such as 6-fluoro trichostatin A, with antiproliferative activities in the micromolar range and with histone deacetylase inhibitory activity.

  18. Stereochemistry of a Rhododaurichromanic Acid Derivative.

    Swamy, Mahadeva M M; Mándi, Attila; Anetai, Masaki; Monde, Kenji

    2016-02-01

    A rhododaurichromanic acid A derivative was synthesized from the naturally occurring daurichromenic acid in enantiomeric pure form. Its absolute configuration was elucidated by applying VCD, ECD and DFT calculations. PMID:27032199

  19. PEGylated DOTA-AHA-based Gd(III) chelates – A relaxometric study

    Fontes, André; Karimib, Shima; Helm, Lothar; Ferreira, Paula M.T.; André, João P.

    2015-01-01

    Three PEGylated derivatives of 1,4,7,10-tetraazacyclododecane-1-((6-amino)hexanoic)-4,7,10-triacetic acid) (DOTA-AHA) with different molecular weights were prepared and characterized. Their Gd(III) chelates were studied in aqueous solution using variable-temperature 1H nuclear magnetic relaxation dispersion (NMRD) and 17ONMR spectroscopy in view of the determination of their relaxivity and the parameters that govern it. The relaxivity varied from 5.1 to 6.5 mM-1.s-1 (37 ºC and 60 MHz) with t...

  20. Development of [90Y]DOTA-conjugated bisphosphonate for treatment of painful bone metastases

    Introduction: Based on the concept of bifunctional radiopharmaceuticals, we have previously developed 186Re-complex-conjugated bisphosphonate analogs for palliation of painful bone metastases and have demonstrated the utility of these compounds. By applying a similar concept, we hypothesized that a bone-specific directed 90Y-labeled radiopharmaceutical could be developed. Methods: In this study, 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was chosen as the chelating site, and DOTA was conjugated with 4-amino-1-hydroxybutylidene-1,1-bisphosphonate. [90Y]DOTA-complex-conjugated bisphosphonate ([90Y]DOTA-HBP) was prepared by coordination with 90Y, and its biodistribution was studied in comparison to [90Y]citrate. Results: In biodistribution experiments, [90Y]DOTA-HBP and [90Y]citrate rapidly accumulated and resided in the bone. Although [90Y]citrate showed a higher level of accumulation in the bone than [90Y]DOTA-HBP, the clearances of [90Y]DOTA-HBP from the blood and from almost all soft tissues were much faster than those of [90Y]citrate. As a result, the estimated absorbed dose ratios of soft tissues to osteogenic cells (target organ) of [90Y]DOTA-HBP were lower than those of [90Y]citrate. Conclusions: [90Y]DOTA-HBP showed superior biodistribution characteristics as a bone-seeking agent and led to a decrease in the level of unnecessary radiation compared to [90Y]citrate. Since the DOTA ligand forms a stable complex not only with 90Y but also with lutetium (177Lu), indium (111In), gallium (67/68Ga), gadolinium (Gd) and so on, complexes of DOTA-conjugated bisphosphonate with various metals could be useful as agents for palliation of metastatic bone pain, bone scintigraphy and magnetic resonance imaging

  1. DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

    Jürgen Grünberg; Simone Jeger; Dikran Sarko; Patrick Dennler; Kurt Zimmermann; Walter Mier; Roger Schibli

    2013-01-01

    Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N'-N''-N'''-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decaly...

  2. DOTA-Functionalized Polylysine: A High Number of DOTA Chelates Positively Influences the Biodistribution of Enzymatic Conjugated Anti-Tumor Antibody chCE7agl

    Grünberg, Jürgen; Jeger, Simone; Sarko, Dikran; Dennler, Patrick; Zimmermann, Kurt; Mier, Walter; Schibli, Roger

    2013-01-01

    Site-specific enzymatic reactions with microbial transglutaminase (mTGase) lead to a homogenous species of immunoconjugates with a defined ligand/antibody ratio. In the present study, we have investigated the influence of different numbers of 1,4,7,10-tetraazacyclododecane-N-N′-N′′-N′′′-tetraacetic acid (DOTA) chelats coupled to a decalysine backbone on the in vivo behavior of the chimeric monoclonal anti-L1CAM antibody chCE7agl. The enzymatic conjugation of (DOTA)1-decalysine, (DOTA)3-decaly...

  3. In vivo evaluation of a radiogallium-labeled bifunctional radiopharmaceutical, Ga-DOTA-MN2, for hypoxic tumor imaging

    On the basis of the findings obtained by X-ray crystallography of gadolinium-diethylenetriamine pentaacetic acid (Ga-DOTA) chelates and the drug design concept of bifunctional radiopharmaceuticals, we previously designed and synthesized a radiogallium-labeled DOTA chelate containing two metronidazole moieties, 67Ga-DOTA-MN2, for hypoxic tumor imaging. As expected, 67Ga-DOTA-MN2 exhibited high in vivo stability, although two carboxyl groups in the DOTA skeleton were conjugated with metronidazole moieties. In this study, we evaluated 67/68Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors. 67Ga-labeling of DOTA-MN2 with 67GaCl3 was achieved with high radiochemical yield (>85%) by 1-min of microwave irradiation (50 W). The pharmacokinetics of 67Ga-DOTA-MN2 were examined in mammary carcinoma (FM3A) tumor-bearing mice, and compared with those of 67Ga-DOTA-MN1 containing one metronidazole unit and '67Ga-DOTA. Upon administration, 67Ga-DOTA-MN2 exhibited higher accumulation in the implanted tumors than '67Ga-DOTA. Tumor-to-blood ratios of 67Ga-DOTA-MN2 were about two-fold higher than those of 67Ga-DOTA-MN1. Autoradiographic analysis showed the heterogeneous localization of '67Ga-DOTA-MN2 in the tumors, which corresponds to hypoxic regions suggested by well-established hypoxia marker drug, pimonidazole. Furthermore, in positron emission tomography (PET) study, the tumors of mice administered '68Ga-labeled DOTA-MN2 were clearly imaged by small-animal PET at 1 h after administration. This study demonstrates the potential usefulness of 67/68Ga-DOTA-MN2 as a nuclear imaging agent for hypoxic tumors and suggests that two functional moieties, such as metronidazole, can be conjugated to radiogallium-DOTA chelate without reducing the complex stability. The present findings provide useful information about the chemical design of radiogallium-labeled radiopharmaceuticals for PET and single photon emission computed tomography (SPECT) studies. (author)

  4. Complexes of salicylic acid and its derivatives

    A generalization and systematization have been made of literature data on complexing of various elements, including beryllium, cadmium, boron, indium, rare-earth elements, actinides, and transition elements with salicylic acid and it derivatives (amino-, nitro- and halosalicylic acids). The effect of the position and nature of the substitute, in the case of salicylic acid derivatives, on the complexing process is discussed. Certain physicochemical properties of the complexes under consideration are described along with data indicative of their stability

  5. [Tl(III)(dota)](-): An Extraordinarily Robust Macrocyclic Complex.

    Fodor, Tamás; Bányai, István; Bényei, Attila; Platas-Iglesias, Carlos; Purgel, Mihály; Horváth, Gábor L; Zékány, László; Tircsó, Gyula; Tóth, Imre

    2015-06-01

    The X-ray structure of {C(NH2)3}[Tl(dota)]·H2O shows that the Tl(3+) ion is deeply buried in the macrocyclic cavity of the dota(4-) ligand (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate) with average Tl-N and Tl-O distances of 2.464 and 2.365 Å, respectively. The metal ion is directly coordinated to the eight donor atoms of the ligand, which results in a twisted square antiprismatic (TSAP') coordination around Tl(3+). A multinuclear (1)H, (13)C, and (205)Tl NMR study combined with DFT calculations confirmed the TSAP' structure of the complex in aqueous solution, which exists as the Λ(λλλλ)/Δ(δδδδ) enantiomeric pair. (205)Tl NMR spectroscopy allowed the protonation constant associated with the protonation of the complex according to [Tl(dota)](-) + H(+) ⇆ [Tl(Hdota)] to be determined, which turned out to be pK(H)Tl(dota) = 1.4 ± 0.1. [Tl(dota)](-) does not react with Br(-), even when using an excess of the anion, but it forms a weak mixed complex with cyanide, [Tl(dota)](-) + CN(-) ⇆ [Tl(dota)(CN)](2-), with an equilibrium constant of Kmix = 6.0 ± 0.8. The dissociation of the [Tl(dota)](-) complex was determined by UV-vis spectrophotometry under acidic conditions using a large excess of Br(-), and it was found to follow proton-assisted kinetics and to take place very slowly (∼10 days), even in 1 M HClO4, with the estimated half-life of the process being in the 10(9) h range at neutral pH. The solution dynamics of [Tl(dota)](-) were investigated using (13)C NMR spectroscopy and DFT calculations. The (13)C NMR spectra recorded at low temperature (272 K) point to C4 symmetry of the complex in solution, which averages to C4v as the temperature increases. This dynamic behavior was attributed to the Λ(λλλλ) ↔ Δ(δδδδ) enantiomerization process, which involves both the inversion of the macrocyclic unit and the rotation of the pendant arms. According to our calculations, the arm-rotation process limits the Λ(λλλλ) ↔

  6. Gadolinium DOTA lysine salt and its diagnostic uses

    The object of this invention is the lysine salt of the complex of gadolinium III of DOTA 1, 4, 7, 10-tetraazacyclododecane-N, N', N'', N'''-tetraacetic acid. This salt having a low toxicity can be used as a contrast agent for magnetic resonance imaging and for X-ray radiography

  7. Gadolinium(III) complexes of mono- and diethyl esters of monophosphonic acid analogue of DOTA as potential MRI contrast agents: solution structures and relaxometric studies

    Lebduskova, Petra; Hermann, Petr; Helm, Lothar; Toth, Eva; Kotek, Jan; Binnemans, Koen; Rudovsky, Jakub; Lukes, Ivan; Merbach, Andre E

    2007-01-01

    Two new macrocyclic DOTA-like chelates containing one phosphonate pendant arm were synthesised as potential contrast agents for MRI ( magnetic resonance imaging). The chelates bind to the lanthanide(III) in an octadentate manner, via four nitrogen atoms, three carboxylate and one phosphonate oxygen atoms. Solution structures of [Ln(do3apO(Et2))(H2O)] and [Ln(do3ap(OEt))(H2O)](-) were studied using P-31 and H-1 NMR spectroscopy and SAP (square-antiprismatic)/TSAP ( twisted square-antiprismatic...

  8. Piperidine nucleoside phosphonic acid derivatives

    Kovačková, Soňa; Dračínský, Martin; Rejman, Dominik

    Praha : Institute of Organic Chemistry and Biochemistry AS CR, v. v. i., 2011 - (Hocek, M.), s. 372-374 ISBN 978-80-86241-37-1. - (Collection Symposium Series. 12). [Chemistry of Nucleic Acid Components /15./. Český Krumlov (CZ), 05.06.2011-10.06.2011] Institutional research plan: CEZ:AV0Z40550506 Keywords : piperidine nucleoside * nucleoside phosphonic acids * nucleoside diphosphate analogs * nucleotide analogs Subject RIV: CC - Organic Chemistry

  9. Folic acid derivatives for use in radioimmunoassay

    The chemical preparation of two folic acid derivatives, labelled with 125I or 131I, is described for use in radioimmunoassay of folic acid and its metabolites in biological fluids such as blood serum. Labelled compounds of the present invention more closely resemble folic acid in that they have glutamic acid in the terminal position. Examples of the use of these compounds in three different assays are given. (U.K.)

  10. Cholic acid derivatives: novel antimicrobials.

    Savage, P B; Li, C

    2000-02-01

    Mimics of squalamine and polymyxin B (PMB) have been prepared from cholic acid in hope of finding new antimicrobial agents. The squalamine mimics include the polyamine and sulphate functionalities found in the parent antibiotic, however, the positions relative to the steroid nucleus have been exchanged. The PMB mimics include the conservation of functionality among the polymyxin family of antibiotics, the primary amine groups and a hydrophobic chain. Although the squalamine and PMB mimics are morphologically dissimilar, they display similar activities. Both are simple to prepare and demonstrate broad spectrum antimicrobial activity against Gram-negative and Gram-positive organisms. Specific examples may be inactive alone, yet effectively permeabilise the outer membranes of Gram-negative bacteria rendering them sensitive to hydrophobic antibiotics. Problems associated with some of the squalamine and PMB mimics stem from their haemolytic activity and interactions with serum proteins, however, examples exist without these side effects which can sensitise Gram-negative bacteria to hydrophobic antibiotics. PMID:11060676

  11. Synthesis of β-Amino Acid Derivatives

    Zhao Yonghua; Ma Zhihua; Jiang Nan; Wang Jianbo

    2004-01-01

    In recent years, β-amino acids and their derivatives have attracted considerable attention due to their occurrence in biologically active natural products, such as dolastatins,cyclohexylnorstatine and Taxol. β-Amino acids also find application in the synthesis of β-lactams,piperidines, indolizidines. Moreover, the peptides consisting of β-amino acids, the so-called β-peptides, have been extensively studied recently. Consequently, considerable efforts have been directed to the synthesis of β-amino acids and their derivatives1. In particular, stereoselective synthesis of β-amino acids has been a challenging project, and there are only limited methods available. In this presentation, we report our efforts in this area.

  12. Gallium-68-DOTA-albumin as a PET blood-pool marker: experimental evaluation in vivo

    Investigations into tumor angiogenesis and antiangiogenic treatment have renewed interest in tumor perfusion. To image tumor blood-pool by PET, suitable tracers are not generally available. In this experimental study, we characterized a 68Ga-labeled 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugate of rat serum albumin (68Ga-DOTA-RSA) in vivo using a generator-produced isotope. Biodistribution was determined in ACI rats after intravenous administration of 3-6 MBq of 68Ga-DOTA-RSA. Three ACI rats were imaged over 1 h by dynamic PET after intravenous administration of 15-25 MBq of 68Ga-DOTA-RSA while the blood-pool activity was recorded simultaneously in a closed extracorporeal loop (ECL) between the carotid artery and the jugular vein. Time-activity curves (TACs) were obtained from volume of interest (VOI) analysis and from the ECL data. Stability and metabolites in plasma and urine were analyzed by size exclusion HPLC (SE-HPLC) 1 h after intravenous injection of 67Ga-DOTA-RSA. Blood radioactivity decreased by 10% and 18% from 10 to 60 min p.i. by biodistribution and PET or ECL, respectively. Tissue sampling between 10 and 60 min p.i. showed slight increases in the uptake of spleen, myocardium, kidney and skeletal muscle while hepatic accretion remained unchanged. Total urinary excretion after 60 min amounted to 9% of the injected dose. HPLC demonstrated a single urinary metabolite corresponding in size to gallium-labeled DOTA. 68Ga-DOTA-RSA is a blood-pool tracer whose physical and biological half-life is well suited for PET. Our findings support clinical imaging using 68Ga-DOTA-labeled human serum albumin (HSA). The generator-produced label makes 68Ga-DOTA-labeled albumin continuously available even to centers lacking an in-house cyclotron

  13. Optimization of time-resolved fluorescence assay for detection of europium-tetraazacyclododecyltetraacetic acid-labeled ligand-receptor interactions.

    De Silva, Channa R; Vagner, Josef; Lynch, Ronald; Gillies, Robert J; Hruby, Victor J

    2010-03-01

    Lanthanide-based luminescent ligand binding assays are superior to traditional radiolabel assays due to improving sensitivity and affordability in high-throughput screening while eliminating the use of radioactivity. Despite significant progress using lanthanide(III)-coordinated chelators such as diethylenetriaminepentaacetic acid (DTPA) derivatives, dissociation-enhanced lanthanide fluoroimmunoassays (DELFIAs) have not yet been successfully used with more stable chelators (e.g., tetraazacyclododecyltetraacetic acid [DOTA] derivatives) due to the incomplete release of lanthanide(III) ions from the complex. Here a modified and optimized DELFIA procedure incorporating an acid treatment protocol is introduced for use with Eu(III)-DOTA-labeled peptides. Complete release of Eu(III) ions from DOTA-labeled ligands was observed using hydrochloric acid (2.0M) prior to the luminescent enhancement step. [Nle(4),d-Phe(7)]-alpha-melanocyte-stimulating hormone (NDP-alpha-MSH) labeled with Eu(III)-DOTA was synthesized, and the binding affinity to cells overexpressing the human melanocortin-4 (hMC4) receptor was evaluated using the modified protocol. Binding data indicate that the Eu(III)-DOTA-linked peptide bound to these cells with an affinity similar to its DTPA analogue. The modified DELFIA procedure was further used to monitor the binding of an Eu(III)-DOTA-labeled heterobivalent peptide to the cells expressing both hMC4 and cholecystokinin-2 (CCK-2) receptors. The modified assay provides superior results and is appropriate for high-throughput screening of ligand libraries. PMID:19852924

  14. Towards the Rational Design of MRI Contrast Agents: δ-Substitution of Lanthanide(III) NB-DOTA-Tetraamide Chelates Influences but Does Not Control Coordination Geometry**

    Carney, Christiane E.; Tran, Anh D.; Jing WANG; Schabel, Matthias C.; Sherry, A. Dean; Woods, Mark

    2011-01-01

    LnDOTA-tetraamide chelates (DOTA=1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) have received considerable recent attention as a result of their potential to act as PARACEST contrast agents for magnetic resonance imaging (MRI). Although PARACEST agents afford several advantages over conventional contrast agents they suffer from substantially higher detection limits; thus, improving the effectiveness of LnDOTA-tetraamide chelates is an important goal. In this study we investigate th...

  15. Synthesis and in vivo evaluation of {sup 201}Tl(III)-DOTA complexes for applications in SPECT imaging

    Hijnen, Nicole M.; Vries, Anke de [Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven (Netherlands); Blange, Roy [Department of Biomolecular Engineering, Antwerp University, 2610 Antwerp (Belgium); Burdinski, Dirk [Department of Biomolecular Engineering, Philips Research, 5656 AE Eindhoven (Netherlands); Gruell, Holger, E-mail: h.gruell@tue.n [Biomedical NMR, Department of Biomedical Engineering, Eindhoven University of Technology, 5600 MB Eindhoven (Netherlands); Department of Biomolecular Engineering, Philips Research, 5656 AE Eindhoven (Netherlands)

    2011-05-15

    Introduction: The aim of this study was to assess the use of {sup 201}thallium{sup 3+} ({sup 201}Tl{sup 3+}) as a radiolabel for nuclear imaging tracers. Methods for labeling of 1,4,7,10-tetraazacyclododecane-N,N',N'',N''' tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) chelators with {sup 201}Tl{sup 3+} were investigated, and the levels of stability of these chelates were tested in vitro and in vivo. Methods: {sup 201}Tl(I)Cl was treated with hydrochloric acid and ozone to form {sup 201}Tl(III)Cl{sub 3}. The procedure for labeling of DOTA and DTPA was optimized, testing different buffer solutions and pH values. The stability levels of {sup 201}Tl(III)-DOTA and {sup 201}Tl(III)-DTPA were assessed in buffer, mouse serum and human serum (1:1, v/v) at a temperature of 310 K for 48 h. Subsequently, in vivo stability studies with {sup 201}Tl(III)-DOTA were performed, comparing the biodistribution of {sup 201}Tl(III)-DOTA with that of {sup 201}Tl(I)Cl in a single-isotope study and with that of {sup 177}Lu(III)-DOTA in a dual-isotope single photon emission computed tomography study. Results: {sup 201}Tl(III)-DTPA, {sup 201}Tl(III)-DOTA and {sup 177}Lu(III)-DOTA were prepared with >95% radiochemical purity. While {sup 201}Tl(III)-DOTA showed a prolonged level of stability in buffer and serum, {sup 201}Tl was quickly released from DTPA in serum. Apart from some urinary excretion, the biodistribution of DOTA-chelated {sup 201}Tl{sup 3+} was similar to that of free (ionic) {sup 201}Tl{sup +} and did not match the biodistribution of {sup 177}Lu(III)-DOTA. This indicated a limited stability of {sup 201}Tl(III)-DOTA complexes in vivo. Conclusion: Despite promising results on the labeling and in vitro stability of {sup 201}Tl(III)-DOTA, our in vivo results indicate that the integrity of {sup 201}Tl(III)-DOTA decreases to <20% during the time required for urinary excretion, thereby limiting the use of {sup 201}Tl{sup 3+} as a

  16. Synthesis and in vivo evaluation of 201Tl(III)-DOTA complexes for applications in SPECT imaging

    Introduction: The aim of this study was to assess the use of 201thallium3+ (201Tl3+) as a radiolabel for nuclear imaging tracers. Methods for labeling of 1,4,7,10-tetraazacyclododecane-N,N',N'',N''' tetraacetic acid (DOTA) and diethylenetriaminepentaacetic acid (DTPA) chelators with 201Tl3+ were investigated, and the levels of stability of these chelates were tested in vitro and in vivo. Methods: 201Tl(I)Cl was treated with hydrochloric acid and ozone to form 201Tl(III)Cl3. The procedure for labeling of DOTA and DTPA was optimized, testing different buffer solutions and pH values. The stability levels of 201Tl(III)-DOTA and 201Tl(III)-DTPA were assessed in buffer, mouse serum and human serum (1:1, v/v) at a temperature of 310 K for 48 h. Subsequently, in vivo stability studies with 201Tl(III)-DOTA were performed, comparing the biodistribution of 201Tl(III)-DOTA with that of 201Tl(I)Cl in a single-isotope study and with that of 177Lu(III)-DOTA in a dual-isotope single photon emission computed tomography study. Results: 201Tl(III)-DTPA, 201Tl(III)-DOTA and 177Lu(III)-DOTA were prepared with >95% radiochemical purity. While 201Tl(III)-DOTA showed a prolonged level of stability in buffer and serum, 201Tl was quickly released from DTPA in serum. Apart from some urinary excretion, the biodistribution of DOTA-chelated 201Tl3+ was similar to that of free (ionic) 201Tl+ and did not match the biodistribution of 177Lu(III)-DOTA. This indicated a limited stability of 201Tl(III)-DOTA complexes in vivo. Conclusion: Despite promising results on the labeling and in vitro stability of 201Tl(III)-DOTA, our in vivo results indicate that the integrity of 201Tl(III)-DOTA decreases to 201Tl3+ as a radiolabel for tracer imaging.

  17. Benzhydroximic Acids - NMR Study of Trimethylsilyl Derivatives

    Schraml, Jan; Kvíčalová, Magdalena; Soukupová, Ludmila; Blechta, Vratislav; Exner, Otto

    2000-01-01

    Roč. 597, 1-2 (2000), s. 200-205. ISSN 0022-328X R&D Projects: GA AV ČR IAA4072605; GA MŠk LB98233 Keywords : trimethylsilyl derivatives * substituted benzhydroximic acids * NMR chemical shifts Subject RIV: CC - Organic Chemistry Impact factor: 1.632, year: 2000

  18. Lithocholic acid and derivatives: Antibacterial activity.

    do Nascimento, Patrícia G G; Lemos, Telma L G; Almeida, Macia C S; de Souza, Juliana M O; Bizerra, Ayla M C; Santiago, Gilvandete M P; da Costa, José G M; Coutinho, Henrique D M

    2015-12-01

    In order to develop bioactive lithocholic acid derivatives, we prepared fifteen semi-synthetic compounds through modification at C-3 and/or C-24. The reactions showed yields ranging from 37% to 100%. The structures of all compounds obtained were identified on the basis of their spectral data (IR, MS, 1D- and 2D-NMR). The activity of lithocholic acid and derivatives was evaluated against the growth of Escherichia coli, Staphylococcus aureus, Bacillus cereus and Pseudomonas aeruginosa. The derivative 3α-formyloxy-5β-cholan-24-oic acid (LA-06) showed the best activity, with MIC values of 0.0790 mM against E. coli (Ec 27) and B. cereus in both cases, and 0.0395 mM against S. aureus (ATCC 12692). Lithocholic acid and the derivatives with MIC⩽1.2 mM were evaluated on the susceptibility of some bacterial pathogens to the aminoglycoside antibiotics neomycin, amikacin and gentamicin was evaluated. There are no previously reported studies about these compounds as modifiers of the action of antibiotics or any other drugs. PMID:26216208

  19. Synthesis of isothiocyanate-derived mercapturic acids

    Vermeulen, M.; Zwanenburg, B.; Chittenden, G.J.F.; Verhagen, H.

    2003-01-01

    Twelve mercapturic acids derived from saturated and unsaturated aliphatic and aromatic isothiocyanates were synthesised, by adding isothiocyanate to a solution of N-acetyl-L-cysteine and sodium bicarbonate, in a typical yield of 77%. Isothiocyanates were synthesised first by adding the corresponding

  20. Identification, characterization and suppression of side-products formed during the synthesis of high dose ⁶⁸Ga-DOTA-TATE.

    Mu, Linjing; Hesselmann, Rolf; Oezdemir, Ufuk; Bertschi, Louis; Blanc, Alain; Dragic, Martina; Löffler, Dirk; Smuda, Christoph; Johayem, Anass; Schibli, Roger

    2013-06-01

    In the course of the establishment of (68)Ga-DOTA-TATE production for clinical use a shoulder comprising presumably several impurities was observed in the chromatogram of the analytical radio-HPLC. LC-MS/MS results support the hypothesis that some of these radioimpurities are radiolytic oxidation by-products of (68)Ga-DOTA-TATE. A new HPLC method was developed for quality control of (68)Ga-DOTA-TATE. Significant improvement on the radiochemical purity of (68)Ga-DOTA-TATE was achieved by the addition of ascorbic acid or ethanol to the reaction mixture. PMID:22939572

  1. Value of 111In-DOTA-lanreotide and 111In-DOTA-DPhe1-Tyr3-octreotide in differentiated thyroid cancer: results of in vitro binding studies and in vivo comparison with 18F-FDG PET

    Radioiodine-negative thyroid cancer presents diagnostic and therapeutic difficulties, warranting the implementation of new imaging and treatment strategies. The purpose of this study was twofold. First, we investigated in vitro the binding characteristics of 111In-DOTA-lanreotide (111In-DOTA-LAN) and 111In-DOTA-DPhe1-Tyr3-octreotide (111In-DOTA-TOC) to cells derived from differentiated thyroid cancer (DTC). Second, we evaluated the value of somatostatin receptor (SSTR) scintigraphy with these radioligands, as compared with 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), for the detection of tumour lesions in DTC patients. Binding of 111In-DOTA-LAN and 111In-DOTA-TOC to cells isolated from surgically removed thyroid tissue was evaluated in vitro by performing saturation and displacement studies. Eighteen DTC patients with elevated thyroglobulin (12 radioiodine-negative, six radioiodine-positive) were investigated with 111In-DOTA-LAN, 111In-DOTA-TOC and 18F-FDG PET scans. Large numbers of SSTR binding sites for 111In-DOTA-LAN and 111In-DOTA-TOC were found on the cells investigated. Both SSTR radioligands exhibited a high binding affinity for these SSTR binding sites. 111In-DOTA-LAN and 111In-DOTA-TOC scintigraphy detected 37 and 33 lesions, respectively, in 17 (94%) patients each, whereas 18F-FDG PET revealed 30 lesions in 15 (83%) patients. Uptake of both SSTR radioligands was found in several radioiodine-negative sites. No striking differences in lesion imaging by 111In-DOTA-LAN and 111In-DOTA-TOC were found. In both radioiodine-negative and radioiodine-positive patients, more lesions were SSTR-positive/18F-FDG-negative than were 18F-FDG-positive/SSTR-negative. Adding a SSTR scan with these radioligands to the diagnostic work-up increases the diagnostic capacity in DTC, and should be considered particularly in radioiodine-negative patients with elevated thyroglobulin levels. (orig.)

  2. Comparative biodistribution of indium- and yttrium-labeled B3 monoclonal antibody conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M-DTPA) or 2-(p-SCN-Bz)-1,4,7,10-tetraazacyclododecane tetraacetic acid (2B-DOTA)

    The biodistribution of indium-111/yttrium-88-labeled B3 monoclonal antibody, a murine IgGlk, was evaluated in non-tumor-bearing mice. B3 was conjugated to either 2-(p-SCN-Bz)-6-methyl-DTPA (1B4M) or 2-(p-SCN-Bz)-1,4,7,10 tetraazacyclododecane tetra-acetic acid (2B-DOTA) and labeled with 111In at 1.4-2.4 mCi/mg and 88Y at 0.1-0.3 mCi/mg. Non-tumor-bearing nude mice were co-injected i.v. with 5-10 μCi/4-10 μg of 111In/88Y-labeled B3 conjugates and sacrificed at 6 h and daily up to 168 h post-injection. Mice injected with 111In/88Y-(1B4M)-B3 showed a similar biodistribution of the two radiolabels in all tissues except the bones, where significantly higher accretion of 88Y than 111In was observed, with 2.8% ± 0.2% vs 1.3% ± 0.16% ID/g in the femur at 168 h, respectively (P111In/88Y-(DOTA)-B3 conjugate showed significantly higher accumulation of 111In than 88Y in most tissues, including the bones, with 2.0% ± 0.1% vs 1.2% ± 0.09% ID/g in the femur at 168 h, respectively (P111In/88Y-(1B4M)-B3 and 0.84, 1.23, 1.56, and 1.31 for 111In/88Y-(DOTA)-B3, respectively, ratios ∼ 1 were observed between 111In-(1B4M)-B3 and 88Y-(DOTA)-B3. In summary, while neither 1B4M nor DOTA was equally stable for 111In and 88Y, the fate of 88Y-(DOTA)-B3 could be closely traced by that of 111In-(1B4M)-B3. (orig.)

  3. Imaging of platelet-derived growth factor receptor β expression in glioblastoma xenografts using affibody molecule 111In-DOTA-Z09591

    TOLMACHEV, VLADIMIR; Varasteh, Zohreh; HONARVAR, HADIS; Hosseinimehr, Seyed Jalal; Eriksson, Olof; Jonasson, Per; Frejd, Fredrik Y.; Abrahmsen, Lars; ORLOVA, ANNA

    2014-01-01

    The overexpression and excessive signaling of platelet-derived growth factor receptor β (PDGFRβ) has been detected in cancers, atherosclerosis, and a variety of fibrotic diseases. Radionuclide in vivo visualization of PDGFRβ expression might help to select PDGFRβ targeting treatment for these diseases. The goal of this study was to evaluate the feasibility of in vivo radionuclide imaging of PDGFRβ expression using an Affibody molecule, a small nonimmunoglobulin affinity protein. Methods The P...

  4. Brown coal derived products ameliorating soil acidity

    Issa, J.; Patti, A.F.; Jackson, W.R. [Monash University, Clayton, Vic. (Australia). Centre for Green Chemistry

    2000-07-01

    Humic acid derived from brown coal, with added calcium, when applied to the soil surface, can increase pH deeper into the soil profile. The humates can move down with water percolating the soil. As they move down the added calcium bound to the humate's cation exchange sites (the acidic oxygen functional groups) can exchange with toxic aluminium ions and ions on exchange sites in the soil. Thus the soil pH is buffered, nutrient transport to plants assisted, and phytotoxic aluminium bound and rendered harmless to plants. K Humate is a commercially available source of humate (ex HRL Agriculture Pty Ltd Australia) derived from brown coal. It can be obtained by the treatment of brown coal with potassium hydroxide. Calsulmag is a commercial treated coal fly ash (also ex HRL Agriculture Pty Ltd) which can be used instead of lime due to its high inorganic calcium and magnesium content. When K humate and Calsulmag are combined in an aqueous mixture, and applied to the surface of an acidic soil, pH is increased (from 3.8 to 4.5) as is exchangeable calcium (30-50%), while exchangeable aluminium is decreased (30-50%), down to a 5 cm depth.

  5. Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

    Park, Ji-Ae, E-mail: jpark@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Lee, Yong Jin; Ko, In Ok [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Tae-Jeong; Chang, Yongmin [Institute of Biomedical Engineering, Kyungpook National University, Daegu (Korea, Republic of); Lim, Sang Moo [Department of Nuclear Medicine, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Kyeong Min [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of); Kim, Jung Young, E-mail: jykim@kirams.re.kr [Molecular Imaging Research Center, Korea Institute of Radiological and Medical Sciences, Seoul (Korea, Republic of)

    2014-12-12

    Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images.

  6. Improved tumor-targeting MRI contrast agents: Gd(DOTA) conjugates of a cycloalkane-based RGD peptide

    Highlights: • Development of improved tumor-targeting MRI contrast agents. • To increase the targeting ability of RGD, we developed cycloalkane-based RGD peptides. • Gd(DOTA) conjugates of cycloalkane-based RGD peptide show improved tumor signal enhancement in vivo MR images. - Abstract: Two new MRI contrast agents, Gd-DOTA-c(RGD-ACP-K) (1) and Gd-DOTA-c(RGD-ACH-K) (2), which were designed by incorporating aminocyclopentane (ACP)- or aminocyclohexane (ACH)-carboxylic acid into Gd-DOTA (gadolinium-tetraazacyclo dodecanetetraacetic acid) and cyclic RGDK peptides, were synthesized and evaluated for tumor-targeting ability in vitro and in vivo. Binding affinity studies showed that both 1 and 2 exhibited higher affinity for integrin receptors than cyclic RGDyK peptides, which were used as a reference. These complexes showed high relaxivity and good stability in human serum and have the potential to improve target-specific signal enhancement in vivo MR images

  7. DOTA-TATE alternative labellings with halogens and radiometals

    Full text: DOTA-D-phe-cys-tyr-D-trp-lys-thr-cys-thr (DOTA-TATE), a somatostatin analog with high affinity for somatostatin receptors expressed in cancer of neuroendocrine origin, may be labeled with different beta radionuclides for its use in targeted radiotherapy. This allows the obtanting of products with particular chemical, radiochemical and biological properties, which interact in specific way with cells that express somatostatin receptors. In this study the labelling of DOTA-TATE with 125I, 131I and 177Lu and their biological properties were investigated, with the aim of potential application as a tumour seeking agents. Radioiodine was introduced on the tyrosyl residue of the DOTA-TATE by oxidation of iodide with chloramine-T. The labeled peptide was isolated from the reaction mixture by sep-pak purification and/or by RP-HPLC. Lutetium-177 was introduced in the peptide via the DOTA ring. To 7,2μg of DOTA-TATE 1mg/mL, 2μL 177LuCl3 (7.2 mCi) and 7.2 μL of gentisic acid in CH3COONa 0.4M were added. The mixture was incubated 30 minutes at 100 deg. C. Purification by RP-HPLC was conducted on a C18 column eluted with a linear gradient from 10% to 40% B in 30 min (A: 0.1% TFA in water and B: 0.1% TFA in acetonitrile). Fractions containing the labeled peptide were pooled and most of the solvent removed by evaporation and re-suspended in 1 mL of saline. For the control of 131I-DOTA-TATE, different gradients were used in order to optimize the separation. In the case of 177Lu-DOTA-TATE analysis, gradient was from 5 to 95% B in 15 minutes. Stability at different time intervals was evaluated by RP-HPLC and by chromatography in ITLC-SG or Whatman 3MM using different mobile phases: 2-butanone (MEK); NaCl 0.9%; EtOH-HCl 0.01N 90:10 and butanol:acetic:H2O (4:1:5) for radioidinated peptides. For 177Lu-DOTA-TATE, the chromatographic systems were: CH3COONH4 10%/MeOH (30:70), BuOH-CH3COOH-H2O (5:2:1), TFA 0,1% in ACN- H2O (1:1) and Sodium citrate 0.1M, pH:5 in Whatman 3MM (Rf

  8. Comparison of the stability of Y-90-, Lu-177- and Ga-68- labeled human serum albumin microspheres (DOTA-HSAM)

    Introduction: Microparticles derived from denatured human serum albumin (DOTA-derivatized human serum albumin microspheres, or DOTA-HSAM) are attractive carriers of radionuclides for both therapeutic and diagnostic purposes. In this article, we describe a labeling procedure for diagnostic (Ga-68) and therapeutic (Y-90, Lu-177) radionuclides and report on the results of stability studies of these products. Methods: DOTA-HSAM was labeled in 0.5 M ammonium acetate buffer, pH 5.0, containing 0.02 mg/ml detergent. After adding the radionuclide, the mixture was shaken for 15 min at 90oC. Labeling yields and in vitro stability were determined by thin-layer chromatography. For determination of the in vivo stability of Ga-68 and Y-90 DOTA-HSAM, the particles were injected intravenously in Wistar rats. Results: Labeling yields up to 95% in the case of Ga-68 and Lu-177 were achieved. Ga-68-labeled DOTA-HSAM showed high in vitro and in vivo stability. The amount of particle-bound radioactivity of Lu-177 DOTA-HSAM declines slowly in a linear manner to approximately 72% after 13 days. For Y-90, the labeling yield decreased with increasing radioactivity level. We presume radiolysis as the reason for these findings. Conclusion: The labeling of DOTA-HSAM with different radionuclides is easy to perform. The radiation-induced cleavage of the labeled chelator together with the rather short half-life of radioactivity fixation in vivo (3.7 days) is, in our opinion, opposed to therapeutic applications of DOTA-HSAM. On the other hand, the high stability of Ga-68 DOTA-HSAM makes them an attractive candidate for the measurement of regional perfusion by PET.

  9. Synthesis of DOTA-conjugated multimeric [Tyr3]octreotide peptides via a combination of Cu(I)-catalyzed "click" cycloaddition and thio acid/sulfonyl azide "sulfo-click" amidation and their in vivo evaluation.

    Yim, C.B.; Dijkgraaf, I.; Merkx, R.; Versluis, C.; Eek, A.; Mulder, G.E.; Rijkers, D.T.; Boerman, O.C.; Liskamp, R.M.

    2010-01-01

    Herein, we describe the design, synthesis, and biological evaluation of a series of DOTA-conjugated monomeric, dimeric, and tetrameric [Tyr(3)]octreotide-based analogues as a tool for tumor imaging and/or radionuclide therapy. These compounds were synthesized using a Cu(I)-catalyzed 1,3-dipolar cycl

  10. [64Cu]-Labelled Trastuzumab: Optimisation of Labelling by DOTA and NODAGA Conjugation and Initial Evaluation in Mice

    Schjøth-Eskesen, Christina; Nielsen, Carsten Haagen; Heissel, Søren;

    2015-01-01

    ,7 acetic acid (NODAGA) analogue in a preliminary HER2 tumour mouse model. The chelators were conjugated to trastuzumab using the activated esters DOTA mono-N-hydroxysuccinimide (NHS) and NODAGA-NHS. (64) Cu-labelling of DOTA-trastuzumab was studied by varying the amount of DOTA-trastuzumab used, reaction...... [(64) Cu]DOTA-trastuzumab and [(64) Cu]NODAGA-trastuzumab were produced after purification with radiochemical purities of >97%. The tracers were injected into mice with HER2 expressing tumours. The mice were imaged by positron emission tomography and showed high tumour uptake of 3-9% ID/g for both......The human epidermal growth factor receptor-2 (HER2) is overexpressed in 20-30% of all breast cancer cases, leading to increased cell proliferation, growth and migration. The monoclonal antibody, trastuzumab, binds to HER2 and is used for treatment of HER2-positive breast cancer. Trastuzumab has...

  11. Preparation, quality control and biodistribution studies of [67Ga]-DOTA-anti-CD20

    Rituximab was successively labeled with [67Ga]-gallium chloride. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 C using DOTA, N-hydroxy succinimide (NHS) in CH2Cl2. DOTA-Rituximab was obtained by the addition of 1 mL of a Rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH=7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 C in 3 h. Radio-thin layer chromatography showed an overall radiochemical purity of 90%-95% at optimized conditions (specific activity = 30 GBq/mg, labeling efficacy; 82%). The final isotonic 67Ga-DOTA-rituximab complex was checked by gel electrophoresis for radiolysis. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rat model performed to determine complex distribution of the radioimmunoconjugate up to 28 h. (orig.)

  12. Pilot study of 68Ga-DOTA-F(ab′)2-trastuzumab in patients with breast cancer

    Beylergil, Volkan; Morris, Patrick G; Smith-Jones, Peter M.; Modi, Shanu; Solit, David; Hudis, Clifford A.; Lu, Yang; O’Donoghue, Joseph; Lyashchenko, Serge K.; Carrasquillo, Jorge A.; Larson, Steven M.; Akhurst, Timothy J.

    2013-01-01

    Objective 68Ga-1,4,7,10-Tetraazacyclododecane-N,N′,N′′,N′′′-tetraacetic acid (DOTA)-F(ab′)2-trastuzumab [68Ga-DOTA-F(ab′)2-trastuzumab] has been developed at our institution as a positron imaging reagent for assessing human epidermal growth factor receptor 2 (HER2) expression status by in-vivo imaging. Initial studies on animals demonstrated promising results in the monitoring of treatment response to heat shock protein 90-targeted drugs that inhibit the client protein HER2. We report here ou...

  13. Caffeic acid derivatives in the roots of yacon (Smallanthus sonchifolius).

    Takenaka, Makiko; Yan, Xiaojun; Ono, Hiroshi; Yoshida, Mitsuru; Nagata, Tadahiro; Nakanishi, Tateo

    2003-01-29

    Five caffeic acid derivatives were found in the roots of yacon, Smallanthus sonchifolius (Poepp. and Endl.) H. Robinson, Asteraceae, as the major water-soluble phenolic compounds. The structures of these compounds were determined by analysis of spectroscopic data. Two of these were chlorogenic acid (3-caffeoylquinic acid) and 3,5-dicaffeoylquinic acid, common phenolic compounds in plants of the family Asteraceae. Three were esters of caffeic acid with the hydroxy groups of aldaric acid, derived from hexose. The structure of the aldaric moiety was determined by hydrolysis and comparison of NMR spectra with those of standard aldaric acids. The compounds were novel caffeic acid esters of altraric acid: 2,4- or 3,5-dicaffeoylaltraric acid, 2,5-dicaffeoylaltraric acid, and 2,3,5- or 2,4,5-tricaffeoylaltraric acid. PMID:12537459

  14. The Adsorption Effect of Quaternized Chitosan Derivatives on Bile Acid

    Shu Xian MENG; Ya Qing FENG; Wen Jin LI; Cai Xia YIN; Jin Ping DENG

    2006-01-01

    Three quaternized chitosan derivatives were synthesized and their adsorption performance of bile acid from aqueous solution was studied. The adsorption capacities and rates of bile acid onto quaternized chitosan derivatives were evaluated. The kinetic experimental data properly correlated with the second-order kinetic model, which indicated that the chemical sorption is the rate-limiting step. The results showed that the quaternized chitosan derivatives are favorable adsorbents for bile acid.

  15. Synthesis and biological evaluation of 177Lu-DOTA-porphyrin conjugate: a potential agent for targeted tumor radiotherapy

    A novel unsymmetrically substituted water soluble porphyrin derivative namely, 5-(p-aminopropylene-oxyphenyl)-10,15,20-tris-(p-carboxymetylene-oxyphenyl) porphyrin was synthesized and coupled with a bifunctional chelating agent, viz. p-NCS-benzyl-DOTA (p-isothiocyanatobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) for developing a suitable conjugate for use in targeted tumor therapy. The porphyrin-p-NCS-benzyl-DOTA conjugate was radiolabeled with 177Lu in good radiolabeling yield. Biodistribution studies performed in Swiss mice bearing fibrosarcoma tumors revealed high tumor uptake (5.33±1.11% injected activity per gm of tumor) within 30 min post-injection. The complex exhibited favorable tumor to blood and tumor to muscle ratios at various post-administration time points. Fast clearance of the non-accumulated activity was observed mostly through the renal pathway. Scintigraphic imaging studies performed in Swiss mice bearing fibrosarcoma tumors also exhibited selective accumulation of activity in the tumor.

  16. Synthesis and antitumor activity of derivatives of 23-hydroxybetulinic acid

    2007-01-01

    A series of natural product 23-hydroxybetulinic acid derivatives were prepared. In the preparation of mono-O-benzoyl ester derivative, it was observed that benzoyl group migrated from 3-O- to 23-O-position during the detritylation.

  17. Selenium- or tellurium- containing bile acids and derivatives thereof

    This invention relates to the preparation of selenium and tellurium derivatives, particularly γ-emitting radioactive derivatives of bile acids and bile salts. Such compounds are valuable in the examination of body function, especially small bowel function. (author)

  18. Intracranial neoplasms: MR imaging with gadolinium - DOTA

    After a review of the capabilities of magnetic resonance without contrast in the diagnostic assessment of intracranial tumors, the authors report the literature and their own experience concerning the use of the paramagnetic contrast agent gadolinium-DOTA in MR imaging. A 0.5 T superconducting system (Toshiba MRT-50A) was used in the evaluation of these tumors. The intravenous administration of gadolinium-DOTA does not substantially increase the sensitivity of MR to primary intra-axial tumors. However, it may provide better delineation of tumor macroscopic extension and separation of the nidus from the surrounding edema. The presence of enhancement reflects areas of alteration of the blood brain barrier and may anticipate malignant changes at the histopathological examination. The role of gadolinium-DOTA administration for differentiation of intra-axial tumor recurrence from parenchyma changes induced by surgery or radiotherapy remains to be established. On the other hand, gadolinium-DOTA dramatically increases the sensitivity and specificity of MR in the investigation of extra-axial primary tumors (meningiomas, neurinomas), sellar tumors and secondary neoplastic lesions as well as in the investigation of their recurrence. Gadolinium-DOTA may be indirectly useful in the identification of the dysontogenetic tumors do not show enhancement as the low grade tumors do. (author)

  19. 86Y-DOTA0-d-Phe1-Tyr3-octreotide (SMT487) - a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion

    The pharmacokinetics and dosimetry of 86Y-DOTA0-d-Phe1-Tyr3-octreotide (86Y-SMT487) were evaluated in a phase I positron emission tomography (PET) study of 24 patients with somatostatin receptor-positive neuroendocrine tumours. The effect of amino acid (AA) co-infusion on renal and tumour uptake was assessed in a cross-over randomised setting. Five regimens were tested: no infusion, 4-h infusion of 120 g mixed AA (26.4 g l-lysine + l-arginine), 4 h l-lysine (50 g), 10 h 240 g mixed AA (52.8 g l-lysine + l-arginine) and 4 h Lys-Arg (25 g each). Comparisons were performed on an intra-patient basis. Infusions of AA started 0.5 h prior to injection of 86Y-SMT487 and PET scans were obtained at 4, 24 and 48 h p.i. Absorbed doses to tissues were computed using the MIRD3 method. 86Y-SMT487 displayed rapid plasma clearance and exclusive renal excretion; uptake was noted in kidneys, tumours, spleen and, to a lesser extent, liver. The 4-h mixed AA co-infusion significantly (P86Y-SMT487 renal uptake by a mean of 21%. This protective effect was significant on the dosimetry data (3.3±1.3 vs 4.4±1.0 mGy/MBq; P90Y-SMT487 (maximum allowed dose: MAD) that would result in a 23-Gy cut-off dose to kidneys was calculated for each study: MAD was higher with mixed AA co-infusion by a mean of 46% (10-114%, P<0.05 vs no infusion). In comparison with 4 h mixed AA, the MAD was higher by a mean of 23% (9-37%; P<0.05) with prolonged infusion and by a mean of 16% (2-28%; P<0.05) with Lys-Arg. We conclude that infusion of large amounts of AA reduces renal exposure during peptide-based radiotherapy and allows higher absorbed doses to tumours. The prolongation of the infusion from 4 to 10 h further enhances the protective effect on the kidneys. (orig.)

  20. Robust labeling and comparative preclinical characterization of DOTA-TOC and DOTA-TATE

    Objectives: Various radionuclide-labeled somatostatin analogues are used currently for diagnosis and therapy of neuroendocrine tumors. In particular, [68Ga]Ga-DOTA-TOC is commonly used for diagnosis, while [177Lu]Lu-DOTA-TATE is used for therapy. With the development of theranostics and personalized medicine where the imaging diagnosis is tailored to the subsequent radiotherapy, it is of paramount importance to investigate the relevance of the ligand exchange. The aim of this study was to compare binding capacity of [67/68Ga]Ga-DOTA-TOC ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecan-1-yl) acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr(ol)) and [67/68Ga]Ga-DOTA-TATE ([67/68Ga]Ga-N-(4,7,10-(tris(carboxymethyl)-1,4,7, 10-tetraazacyclododecan-1-yl)acetyl-D-Phe-c[Cys-D-Tyr-Trp-Lys-Thr-Cys]-Thr) in vitro in monkey brain cryosections and in vivo in the rat, where, in contrast to transfected cell lines, there is a heterogeneous distribution of somatostatin receptor (SSTR) subtypes. The influence of various production methods of [68Ga]Ga-DOTA-TOC and [68Ga]Ga-DOTA-TATE on the biological performance of the tracers was also studied. Material and Methods: [67Ga]Ga-DOTA-TOC, [68Ga]Ga-DOTA-TOC, [67Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TATE were synthesized including preconcentration and purification of the generator eluate. The binding of the radioligands was assessed in vitro using autoradiography on cryosections of Rhesus monkey brains and in vivo/ex vivo using organ distribution studies in rats. Results and Discussion: The tracer production method was improved in terms of higher robustness, simplification and good manufacturing practice (GMP) relevance. The synthesis variation did not influence the biological performance of the tracers. There was no statistically significant difference observed in the binding of [67/68Ga]Ga-DOTA-TOC and [67/68Ga]Ga-DOTA-TATE either in brain cortex in vitro or in rat biodistribution and uptake in SSTR-positive tissues

  1. 68Ga-DOTA-NOC somatostatin receptor-targeting imaging in pancreatic carcinoma

    Objective: To synthesize 68Ga-1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid-1-Nal3-octreotide (DOTA-NOC) as a new generation of positron emitting radionuclide labeled somatostatin analogue, and perform 68Ga-DOTA-NOC micro PET imaging on CFPAC-1 pancreatic cancer bearing nude mice. Methods: Thirty-seven MBq (100 μl) GaCl3 and 20 μg DOTA-NOC were added into 20 μl hydroxyethyl piperazine ethanesulfonic acid (HEPES) solution (0.1 mmol/L, pH=5.0), and heated for 15 min at 95 ℃. The radiochemical purity and in vitro stability of 68Ga-DOTA-NOC were analyzed with HPLC. Fifteen normal BALB/c mice were injected with 3.7 MBq 68Ga-DOTA-NOC via tail vein, and the biodistribution in dissected organs were measured at 5, 15, 30, 60 and 120 min respectively after the injection. CFPAC-1 pancreatic cancer cells were co-incubated with 68Ga-DOTA-NOC and the specific uptake ability was calculated. 68Ga-DOTA-NOC was injected into nude mice bearing CFPAC-1 tumors via tail vain. Dynamic and static images were performed by micro PET. ROI was drawn to calculate the T/NT and access TAC in tumor and main organs. The expression of SSTR (1-5) in CFPAC-1 cells in vivo was observed by flow cytometry. The correlation between the expression of SSTR and the T/NT was analyzed by linear correlation analysis. Results: 68Ga-NOTA-NOC had high radiolabeling yield of (98.8± 1.0)% and stability. Biodistribution study demonstrated that the predominant uptake of 68Ga-DOTA-NOC was found in the kidneys ((11.20±0.32) %ID/g at 5 min and (4.11±0.21) %ID/g at 60 min, respectively). The pancreas, lungs and stomach also showed high uptake. 68Ga-DOTA-NOC could be specifically uptaken by CFPAC-1 cells with high affinity. T/NT of 68Ga-DOTA-NOC in CFPAC-1 cancer xenografts was 3.2 ± 0.2 at 120 min post-injection. SSTR 1, 2, 4, 5 expressed in CFPAC-1 cells and xenograft tissues were (96.83± 1.23)%, (99.73±0.98)%, (90.42±0.63)% and (92.96±0.71)%, respectively. The SSTR 2, 5 expression level and

  2. Preparation and biological studies of 68Ga-DOTA-alendronate

    Ashraf Fakhari; Amir Jalilian; Fariba Johari-daha; Mehdi Shafiee-Ardestani; Ali Khalaj

    2016-01-01

    Objective(s): In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga).Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95°C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation,biodistribution studies,...

  3. Assessment of blood flow with 68Ga-DOTA PET in experimental inflammation: a validation study using 15O-water

    Autio, Anu; Saraste, Antti; Kudomi, Nobuyuki; Saanijoki, Tiina; Johansson, Jarkko; Liljenbäck, Heidi; Tarkia, Miikka; Oikonen, Vesa; Sipilä, Hannu T; Roivainen, Anne

    2014-01-01

    Increased blood flow and vascular permeability are key events in inflammation. Based on the fact that Gadolinium-1,4,7,10-tetraazacyclododecane-N,N‘,N‘‘,N‘‘‘-tetraacetic acid (Gd-DOTA) is commonly used in magnetic resonance (MR) imaging of blood flow (perfusion), we evaluated the feasibility of its Gallium-68 labeled DOTA analog (68Ga-DOTA) for positron emission tomography (PET) imaging of blood flow in experimental inflammation. Adult, male Sprague-Dawley rats with turpentine oil induced ste...

  4. Synthesis and evaluation of 68Ga-labeled DOTA-2-deoxy-D-glucosamine as a potential radiotracer in μPET imaging

    Yang, Zhi; Xiong, Chiyi; Zhang, Rui; Zhu, Hua; Li, Chun

    2012-01-01

    The purposes of this study were to develop an efficient method of labeling D-glucosamine hydrochloride with gallium 68 (68Ga) and investigate the imaging properties of the resulting radiotracer in a human tumor xenograft model using micro-positron emission tomography (μPET). The precursor compound 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-2-deoxy-D-glucosamine (DOTA-DG) was synthesized from D-glucosamine hydrochloride and 2-(4-isothiocyanatobenzyl)-DOTA. Radiolabeling of...

  5. Acetylcholinesterase inhibitory properties of some benzoic acid derivatives

    Yildiz, Melike; Kiliç, Deryanur; Ünver, Yaǧmur; Şentürk, Murat; Askin, Hakan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Acetylcholinesterase (AChE) hydrolyses the neurotransmitter acetylcholine to acetic acid and choline. AChE inhibitors are used in treatment of several neurodegeneartive disorder and Alzheimer's disease. In the present study, inhibition of AChE with some benzoic acid derivatives were investigated. 3-Chloro-benzoic acid (1), 2-hydroxy-5-sulfobenzoic acid (2), 2-(sulfooxy) benzoic acid (3), 2-hydroxybenzoic acid (4), 2,3-dimethoxybenzoic (5), and 3,4,5-trimethoxybenzoic (6) were calculated IC50 values AChE enzyme. Kinetic investigations showed that similarly to AChE inhibitors. Benzoic acid derivatives (1-6) investigated are encouraging agents which may be used as lead molecules in order to derivative novel AChE inhibitors that might be useful in medical applications.

  6. Determination of Ascorbic Acid in Vegetables by Derivative Spectrophotometry

    Aydoğmuş, Zeynep; ÇETİN, Sevil Müge

    2002-01-01

    Determination of ascorbic acid (AA) in garlic, green pepper and chestnut was performed by derivative spectrophotometry without using any pre-separation or background correction techniques. The method is based on the measurement of the distances between two extremum values (peak-to-peak amplitudes) in second and third order derivative spectra of the extracts. Ten percent trichloroacetic acid was found to be the most suitable extraction solution. In the second order derivative spectru...

  7. 68Ga-autoclabeling of DOTA-TATE and DOTA-NOC

    Blom, Elisabeth; Koziorowski, Jacek

    2012-01-01

    A new method combining (68)Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC.......A new method combining (68)Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC....

  8. Natural Cinnamic Acids, Synthetic Derivatives and Hybrids with Antimicrobial Activity

    Juan David Guzman

    2014-11-01

    Full Text Available Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships.

  9. Natural cinnamic acids, synthetic derivatives and hybrids with antimicrobial activity.

    Guzman, Juan David

    2014-01-01

    Antimicrobial natural preparations involving cinnamon, storax and propolis have been long used topically for treating infections. Cinnamic acids and related molecules are partly responsible for the therapeutic effects observed in these preparations. Most of the cinnamic acids, their esters, amides, aldehydes and alcohols, show significant growth inhibition against one or several bacterial and fungal species. Of particular interest is the potent antitubercular activity observed for some of these cinnamic derivatives, which may be amenable as future drugs for treating tuberculosis. This review intends to summarize the literature data on the antimicrobial activity of the natural cinnamic acids and related derivatives. In addition, selected hybrids between cinnamic acids and biologically active scaffolds with antimicrobial activity were also included. A comprehensive literature search was performed collating the minimum inhibitory concentration (MIC) of each cinnamic acid or derivative against the reported microorganisms. The MIC data allows the relative comparison between series of molecules and the derivation of structure-activity relationships. PMID:25429559

  10. 68Ga-DOTA-NGR as a novel molecular probe for APN-positive tumor imaging using MicroPET

    Aminopeptidase N (APN) is selectively expressed on many tumors and the endothelium of tumor neovasculature, and may serve as a promising target for cancer diagnosis and therapy. Asparagine–glycine–arginine (NGR) peptides have been shown to bind specifically to the APN receptor and have served as vehicles for the delivery of various therapeutic drugs in previous studies. The purpose of this study was to synthesize and evaluate the efficacy of a 68Ga-labeled NGR peptide as a new molecular probe that binds to APN. Methods: NGR peptide was conjugated with 1,4,7,10-tetraazacyclododecane-N,N’,N”,N”’-tetraacetic acid (DOTA) and labeled with 68Ga at 95 °C for 10 min. In vitro uptake and binding analysis was performed with A549 and MDA-MB231 cells. Biodistribution of 68Ga-DOTA-NGR was determined in normal mice by dissection method. 68Ga-DOTA-NGR PET was performed in A549 and MDA-MB231 xenografts, and included dynamic and static imaging. APN expression in tumors and new vasculatures was analyzed by immunohistochemistry. Results: The radiochemical purity of 68Ga-DOTA-NGR was 98.0% ± 1.4% with a specific activity of about 17.49 MBq/nmol. The uptake of 68Ga-DOTA-NGR in A549 cells increased with longer incubation times, and could be blocked by cold DOTA-NGR, while no specific uptake was found in MDA-MB231 cells. In vivo biodistribution studies showed that 68Ga-DOTA-NGR was mainly excreted from the kidney, and rapidly cleared from blood and nonspecific organs. MicroPET imaging showed that high focal accumulation had occurred in the tumor site at 1 h post-injection (pi) in A549 tumor xenografts. A significant reduction of tumor uptake was observed following coinjection with a blocking dose of DOTA-NGR, whereas only mild uptake was found in MDA-MB231 tumor xenografts. Tumor uptake, measured as the tumor/lung ratio, increased with time peaking at 12.58 ± 1.26 at 1.5 h pi. Immunohistochemical staining confirmed that APN was overexpressed on A549 cells and

  11. Conformational Interconversions of Amino Acid Derivatives

    Kaminský, Jakub; Jensen, F.

    2016-01-01

    Roč. 12, č. 2 (2016), s. 694-705. ISSN 1549-9618 R&D Projects: GA ČR GA13-03978S; GA ČR(CZ) GA14-03564S Institutional support: RVO:61388963 Keywords : amino acids * force fields * transition states Subject RIV: CF - Physical ; Theoretical Chemistry Impact factor: 5.498, year: 2014

  12. Rapid intracerebroventricular delivery of Cu-DOTA-etanercept after peripheral administration demonstrated by PET imaging

    Chen Xiaoyuan

    2009-02-01

    Full Text Available Abstract Background The cytokines interleukin-1 and tumor necrosis factor (TNF, and the cytokine blocker interleukin-1 receptor antagonist, all have been demonstrated to enter the cerebrospinal fluid (CSF following peripheral administration. Recent reports of rapid clinical improvement in patients with Alzheimer's disease and related forms of dementia following perispinal administration of etanercept, a TNF antagonist, suggest that etanercept also has the ability to reach the brain CSF. To investigate, etanercept was labeled with a positron emitter to enable visualization of its intracranial distribution following peripheral administration by PET in an animal model. Findings Radiolabeling of etanercept with the PET emitter 64Cu was performed by DOTA (1,4,7,10-tetraazadodecane-N,N',N",N"'-tetraacetic acid conjugation of etanercept, followed by column purification and 64Cu labeling. MicroPET imaging revealed accumulation of 64Cu-DOTA-etanercept within the lateral and third cerebral ventricles within minutes of peripheral perispinal administration in a normal rat anesthesized with isoflurane anesthesia, with concentration within the choroid plexus and into the CSF. Conclusion Synthesis of 64Cu-DOTA-etanercept enabled visualization of its intracranial distribution by microPET imaging. MicroPET imaging documented rapid accumulation of 64Cu-DOTA-etanercept within the choroid plexus and the cerebrospinal fluid within the cerebral ventricles of a living rat after peripheral administration. Further study of the effects of etanercept and TNF at the level of the choroid plexus may yield valuable insights into the pathogenesis of Alzheimer's disease.

  13. Synthesis of azo derivatives of 4-aminosalicylic acid

    Zheng Bao Zhao; Hui Xia Zheng; Yuan Gui Wei; Jiang Liu

    2007-01-01

    For searching a better 4-aminosalicylic acid derivative with higher activity and less side effects against the inflammatory bowel disease, 4-aminosalicylic acid (4-ASA) was protected by benzyloxycarbonyl and acetyl, respectively.The resultant was hydrogenized to remove protective group of amino group, then the product was reacted with NaNO2 to give diazonium salt, which was conjugated with salicylic acid, hydroxybenzene, N-salicyloyl glycine acid to get azo derivatives of 4-ASA.The azo derivatives were hydrolyzed under the alkaline condition to get the target products.All compounds were characterized by FT-IR, 1H NMR, 13C NMR spectra in details.New derivatives of 4-ASA were characterized.The synthetic route was reasonable and feasible.

  14. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    Orcutt, Kelly Davis; Slusarczyk, Adrian L. [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Cieslewicz, Maryelise [Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Ruiz-Yi, Benjamin [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Bhushan, Kumar R. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Frangioni, John V. [Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Department of Radiology, Beth Israel Deaconess Medical Center, Boston, MA 02215 (United States); Wittrup, K. Dane, E-mail: wittrup@mit.ed [Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States); Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139 (United States)

    2011-02-15

    Introduction: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. Methods: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). Results: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2{+-}1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a {sup 111}In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals.

  15. Engineering an antibody with picomolar affinity to DOTA chelates of multiple radionuclides for pretargeted radioimmunotherapy and imaging

    Introduction: In pretargeted radioimmunotherapy (PRIT), a bifunctional antibody is administered and allowed to pre-localize to tumor cells. Subsequently, a chelated radionuclide is administered and captured by cell-bound antibody while unbound hapten clears rapidly from the body. We aim to engineer high-affinity binders to 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelates for use in PRIT applications. Methods: We mathematically modeled antibody and hapten pharmacokinetics to analyze hapten tumor retention as a function of hapten binding affinity. Motivated by model predictions, we used directed evolution and yeast surface display to affinity mature the 2D12.5 antibody to DOTA, reformatted as a single chain variable fragment (scFv). Results: Modeling predicts that for high antigen density and saturating bsAb dose, a hapten-binding affinity of 100 pM is needed for near-maximal hapten retention. We affinity matured 2D12.5 with an initial binding constant of about 10 nM to DOTA-yttrium chelates. Affinity maturation resulted in a 1000-fold affinity improvement to biotinylated DOTA-yttrium, yielding an 8.2±1.9 picomolar binder. The high-affinity scFv binds DOTA complexes of lutetium and gadolinium with similar picomolar affinity and indium chelates with low nanomolar affinity. When engineered into a bispecific antibody construct targeting carcinoembryonic antigen, pretargeted high-affinity scFv results in significantly higher tumor retention of a 111In-DOTA hapten compared to pretargeted wild-type scFv in a xenograft mouse model. Conclusions: We have engineered a versatile, high-affinity, DOTA-chelate-binding scFv. We anticipate it will prove useful in developing pretargeted imaging and therapy protocols to exploit the potential of a variety of radiometals.

  16. Somatostatin-based radiopeptide therapy with [177Lu-DOTA]-TOC versus [90Y-DOTA]-TOC in neuroendocrine tumours

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides 90Y or 177Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [90Y-DOTA]-TOC or [177Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [90Y-DOTA]-TOC and 141 patients underwent 259 cycles of [177Lu-DOTA]-TOC. The median survival after [177Lu-DOTA]-TOC and after [90Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [177Lu-DOTA]-TOC over [90Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [177Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [177Lu-DOTA]-TOC and [90Y-DOTA]-TOC. Furthermore, [177Lu-DOTA]-TOC was less haematotoxic than [90Y-DOTA]-TOC. (orig.)

  17. Amino acid derived 1,4-dialkyl substituted imidazolones

    Diness, Frederik; Meldal, Morten Peter

    2010-01-01

    A general method for synthesis of 1,4-substituted imidazolones from amino acids on solid support or in solution has been developed. Amino acid derived 3-Boc-(1,3)-oxazinane (Box) protected amino aldehyde building blocks were coupled through urea bonds to the amino terminal of dipeptides or amino...

  18. Caffeic Acid Derivatives in Dried Lamiaceae and Echinacea purpurea Products

    The concentrations of caffeic acid derivatives within Lamiaceae and Echinacea (herb, spice, tea, and dietary supplement forms) readily available in the U.S. marketplace (n=72) were determined. After the first identification of chicoric acid in Ocimum basilicum (basil), the extent to which chicoric a...

  19. Experimental MR imaging with Gd-DOTA: Preliminary results

    To evaluate the paramagnetic properties of a new gadolinium chelate, Gd-DOTA, in vitro and in vivo MR imaging was performed with a 0.5-T supraconductive magnet. The in vitro study consisted in measuring the MR signal obtained with various concentrations of Gd-DOTA and Gd-DTPA in different solutions. Potentialization of the paramagnetic properties of both DOTA and DTPA can be achieved by deuterium, glycerol, and protein solutions. The in vivo study was performed in rabbits with various experimental lesions. Enhancement of anatomic details was obtained with both Gd-DOTA and Gd-DTPA. There was no significant difference between Gd-DOTA and Gd-DTPA, both for in vitro and in vivo experiments. Gd-DOTA appears to be a potential paramagnetic agent for MR imaging

  20. Preparation and Preliminary Biological Evaluation of {sup 177}Lu-DOTA folate as Potential Folate Receptor Targeting Therapeutic Agent

    Choi, Kang-Hyuk; Hong, Young-Don; Pyun, Mi-Sun; Lee, So-Young; Felipe, Fenelope; Yoon, Sun-Ha; Choi, Sun-Ju [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2008-10-15

    Folic Acid (FA) and FA derivatives are overexpressed on several tumor cells. The cell-membrane folic acid receptors are known to be responsible for the cellular accumulation of FA and FA analogs, such as methotrexate and folic acid. Folate has been characterized to have high affinity for the folate-receptor positive cells and tissues and considered to be useful as diagnostic imaging and therapeutic agent. In 1940s, Folate analogue, aminopterin, was first used for treatment of leukemia and recently, many folate derivatives were tried for cancer-treatment agent as well as visualization of folate receptor. Many researchers tried to conjugate folic acid with macromolecules or low molecular weight chelators through its alpha or gamma carboxylate. However, despite the reduced binding affinity, FAs are still recognized by the folate receptor. Therefore, we focused to develop folate-based radiopharmaceutical that has the potential to be used as a therapeutic agent. We report here the synthesis and the radiolabeling of {sup 177}Lu-DOTA as well as the biodistribution data of our developed compound.

  1. Development of 177Lu-DOTA-anti-CD20 for radioimmunotherapy

    Rituximab was successively labeled with 177Lu-lutetium chloride. 177Lu chloride was obtained by thermal neutron flux (4 x 1013 n cm-2 s-1) of natural Lu2O3 sample with a specific activity of 2.6-3 GBq/mg. The macrocyclic bifunctional chelating agent, N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 deg C using DOTA, N-hydroxy succinimide (NHS) in CH2Cl2. DOTA-rituximab was obtained by the addition of 1 mL of a rituximab pharmaceutical solution (5 mg/mL, in phosphate buffer, pH 7.8) to a glass tube pre-coated with DOTA-NHS (0.01-0.1 mg) at 25 deg C with continuous mild stirring for 15 h. Radiolabeling was performed at 37 deg C in 24 h. Radio-thin layer chromatography showed an overall radiochemical purity of >98% at optimized conditions (specific activity = 444 MBq/mg, labeling efficacy; 82%). The final isotonic 177Lu-DOTA-rituximab complex was checked by gel electrophoresis for structure integrity control. Radio-TLC was performed to ensure that only one species was present after filtration through a 0.22 μm filter. Preliminary biodistribution studies in normal rats were carried out to determine complex distribution of the radioimmunoconjugate up to 168 h. The biodistribution data were in accordance with other antiCD20 radioimmunoconjugates already reported. (author)

  2. Direct amidation of amino acid derivatives catalyzed by arylboronic acids : applications in dipeptide synthesis.

    Liu, S.; Yang, Y.; Liu, X.; Ferdousi, F. K.; Batsanov, A.S.; Whiting, A

    2013-01-01

    The direct amidation of amino acid derivatives catalyzed by arylboronic acids has been examined. The reaction was generally slow relative to simple amine-carboxylic acid combinations though proceeded at 65–68 °C generally avoiding racemization. 3,4,5-Trifluorophenylboronic and o-nitrophenylboronic acids were found to be the best catalysts, though for slower dipeptide formations, high catalyst loadings were required and an interesting synergistic catalytic effect between two arylboronic acids ...

  3. Interaction Mechanism of Anthracene with Benzoic Acid and Its Derivatives

    HE Ying-Ying; WANG Xiao-Chang; FAN Xiao-Yuan; ZHAO Bo; JIN Peng-Kang

    2008-01-01

    Interaction mechanism of anthracene, one of the typical polycyclic aromatic hydrocarbons, with benzoic acid and its hydroxyl-substituted derivatives, o-hydroxylbenzoic acid and p-hydroxylbenzoic acid, were studied using FFIR, UV and fluorescence spectra. The experiments confirmed that there was a specific and oriented interaction between anthracene and the aromatic carboxylic acids, and the bonding mode depended on both the chemical struc- ture of reactants and acidity of solution. The π-H hydrogen bond played a main role in the interaction between an-thracene and the aromatic carboxylic proton of benzoic acid or o-hydroxylbenzoic acid when pH≤pK, and the π-π electron donor-acceptor (EDA) interaction increasingly became the main binding mode when pH>pK. The de-crease of interaction intensity of benzoic acid was observed by introducing hydroxyl at its ortho position. The spe-cial D-π-A structure of p-hydroxylbenzoic acid made it easy to form the planar multi-molecule congeries that could interact with anthracene, so the interaction between anthracene and p-hydroxylbenzoic acid always followed the π-π EDA model no matter the solution acidity. For p-hydroxylbenzoic acid, the π-π interaction mode remained un-changed when pH increased from 2.0 to 10.0, and the binding intensity was higher than that between benzoic acid and anthracene because of the formation of the multi-molecule congeries.

  4. Synthesis and mesomorphic behaviour of lithocholic acid derivatives

    V A E Shaikh; N N Maldar; S V Lonikar

    2003-08-01

    A series of liquid crystalline derivatives of lithocholic acid were prepared using simple chemical reactions involving the terminal functional group—hydroxyl at C-3 and/or carboxyl at C-24. Thus methyl -3-(3-carboxy propionyl) lithocholate (I), 3-(3-carboxy propionyl) lithocholic acid (II), 3-acetyl lithocholic acid (III), 3-propionyl lithocholic acid (IV), 3-benzoyl lithocholic acid (V), 3-(4-nitrobenzoyl) lithocholic acid (VI), 3-cinnamoyl lithocholic acid (VII), methyl-3-(4-nitrobenzoyl) lithocholate (VIII) and 1,4-bis [cholan-24-methoxy carbonyl-3-oxycarbonyl] butane (IX) were prepared in good yields and characterized by IR, NMR and polarizing optical microscopy. Compounds (I) and (IX) exhibited monotropic behaviour while the others were enantiotropic. Some of the compounds also showed a high tendency of super cooling. Compounds (V), (VI) and (IX) formed cholesteric phase while the remaining compounds displayed smectic phase.

  5. Lutetium-177 complexation of DOTA and DTPA in the presence of competing metals

    As part of basic studies on bifunctional chelating agents for 177Lu-labeled antibodies, 177Lu complexation of 1,4,7,10-tetraazacyclododecan-N,N',N',N'''-tetraacetic acid (DOTA) and diethylenetriamine-N,N,N',N',N'-pentaacetic acid (DTPA) was investigated in the presence of competing metals, including Ca(II), Fe(II), and Zn(II). It was found that DTPA is a better 177Lu complexation agent than DOTA in the presence of Ca(II), Fe(II), and Zn(II). Moreover, the elimination of Fe from the 177Lu solution proved especially effective because the DTPA complexation of 177Lu was highly inhibited by Fe(II). (author)

  6. Oleanolic acid and related derivatives as medicinally important compounds.

    Sultana, Nighat; Ata, Athar

    2008-12-01

    Oleanolic acid has been isolated from chloroform extract of Olea ferruginea Royle after removal of organic bases and free acids. The literature survey revealed it to be biologically very important. In this review the biological significance of oleanolic acid and its derivatives has been discussed. The aim of this review is to update current knowledge on oleanolic acid and its natural and semisynthetic analogs, focussing on its cytotoxic, antitumer, antioxidant, anti-inflamatory, anti-HIV, acetyl cholinesterase, alpha-glucosidase, antimicrobial, hepatoprotective, anti-inflammatory, antipruritic, spasmolytic activity, anti-angiogenic, antiallergic, antiviral and immunomodulatory activities. We present in this review, for the first time, a compilation of the most relevant scientific papers and technical reports of the chemical, pre-clinical and clinical research on the properties of oleanolic acid and its derivatives. PMID:18618318

  7. Conformational Interconversions of Amino Acid Derivatives.

    Kaminský, Jakub; Jensen, Frank

    2016-02-01

    Exhaustive conformational interconversions including transition structure analyses of N-acetyl-l-glycine-N-methylamide as well as its alanine, serine, and cysteine analogues have been investigated at the MP2/6-31G** level, yielding a total of 142 transition states. Improved estimates of relative energies were obtained by separately extrapolating the Hartree-Fock and MP2 energies to the basis set limit and adding the difference between CCSD(T) and MP2 results with the cc-pVDZ basis set to the extrapolated MP2 results. The performance of eight empirical force fields (AMBER94, AMBER14SB, MM2, MM3, MMFFs, CHARMM22_CMAP, OPLS_2005, and AMOEBAPRO13) in reproducing ab initio energies of transition states was tested. Our results indicate that commonly used class I force fields employing a fixed partial charge model for the electrostatic interaction provide mean errors in the ∼10 kJ/mol range for energies of conformational transition states for amino acid conformers. Modern reparametrized versions, such as CHARMM22_CMAP, and polarizable force fields, such as AMOEBAPRO13, have slightly lower mean errors, but maximal errors are still in the 35 kJ/mol range. There are differences between the force fields in their ability for reproducing conformational transitions classified according to backbone/side-chain or regions in the Ramachandran angles, but the data set is likely too small to draw any general conclusions. Errors in conformational interconversion barriers by ∼10 kJ/mol suggest that the commonly used force field may bias certain types of transitions by several orders of magnitude in rate and thus lead to incorrect dynamics in simulations. It is therefore suggested that information for conformational transition states should be included in parametrizations of new force fields. PMID:26691979

  8. Effect of amino acids and amino acid derivatives on crystallization of hemoglobin and ribonuclease A

    The effect of the addition of amino acids and amino acid derivatives on the crystallization of hemoglobin and ribonuclease A has been evaluated. The results showed that certain types of additives expand the concentration conditions in which crystals are formed. Determination of the appropriate conditions for protein crystallization remains a highly empirical process. Preventing protein aggregation is necessary for the formation of single crystals under aggregation-prone solution conditions. Because many amino acids and amino acid derivatives offer a unique combination of solubility and stabilizing properties, they open new avenues into the field of protein aggregation research. The use of amino acids and amino acid derivatives can potentially influence processes such as heat treatment and refolding reactions. The effect of the addition of several amino acids, such as lysine, and several amino acid derivatives, such as glycine ethyl ester and glycine amide, on the crystallization of equine hemoglobin and bovine pancreatic ribonuclease A has been examined. The addition of these amino acids and amino acid derivatives expanded the range of precipitant concentration in which crystals formed without aggregation. The addition of such additives appears to promote the crystallization of proteins

  9. Effect of amino acids and amino acid derivatives on crystallization of hemoglobin and ribonuclease A

    Ito, Len, E-mail: len@ksc.kwansei.ac.jp; Kobayashi, Toyoaki [School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan); Shiraki, Kentaro [Institute of Applied Physics, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8573 (Japan); Yamaguchi, Hiroshi [School of Science and Technology, Kwansei Gakuin University, 2-1 Gakuen, Sanda, Hyogo 669-1337 (Japan)

    2008-05-01

    The effect of the addition of amino acids and amino acid derivatives on the crystallization of hemoglobin and ribonuclease A has been evaluated. The results showed that certain types of additives expand the concentration conditions in which crystals are formed. Determination of the appropriate conditions for protein crystallization remains a highly empirical process. Preventing protein aggregation is necessary for the formation of single crystals under aggregation-prone solution conditions. Because many amino acids and amino acid derivatives offer a unique combination of solubility and stabilizing properties, they open new avenues into the field of protein aggregation research. The use of amino acids and amino acid derivatives can potentially influence processes such as heat treatment and refolding reactions. The effect of the addition of several amino acids, such as lysine, and several amino acid derivatives, such as glycine ethyl ester and glycine amide, on the crystallization of equine hemoglobin and bovine pancreatic ribonuclease A has been examined. The addition of these amino acids and amino acid derivatives expanded the range of precipitant concentration in which crystals formed without aggregation. The addition of such additives appears to promote the crystallization of proteins.

  10. Therapy of neuroendocrine carcinoma with Y-90 DOTA- preliminary results

    Full text: Aim: Cell membrane-specific somatostatin receptors are usually expressed by neuroendocrine tumors. Radiolabelled receptor-binding somatostatin analogues target tissues expressing these receptors and can be used for visualization and treatment. After the localization of tumors bearing somatostatin receptors with 111In or 99mTc labeled somatostatin analogues, in the case of high tumor uptake related to non target tissues, different radioisotopes have been used for their treatment. Thus, application of high doses of 111In- DTPA-octreotide had an impact on improvement of the clinical symptoms, without significant reduction of the tumor mass. However, 90Y somatostatin analogues (DOTA TOC, lanreotide) may be more effective for reduction of the tissue of the larger tumors while 177Lu labeled ones may be applied in smaller tumors. Combination of both of them seems to be the most effective therapy, particularly in tumors bearing both small and large lesions. The aim of this work is presentation of the preliminary results of the therapy of NETs with another octreotide analogue, 90Y DOTA TATE, which so far has been proved to have high therapeutic potential when labeled with 177Lu. Patients and methods: We investigated 7 patients with neuroendocrine tumors (two patients had neuroendocrine pancreatic carcinomas with liver metastases (one of them had metastases in peritoneal lymph nodes), one patient with operated (resected) bronchial carcinoid and liver metastases, three patients with neuroendocrine carcinomas of unknown origin and hepatic metastases (one with skeletal metastases) and one with pancreatic gastrinoma without metastases (surgery was impossible to perform). In all of them, together with other laboratory analyses and imaging methods, scintigraphy with somatostatin analogues was performed (in 3 with 111In Octreoscan and in the other 4 with 99mTc HYNIC TOC) and high tumor uptake was observed. The therapy was performed with 2- 4,5 GBq 90Y DOTA TATE per

  11. Design, Synthesis, and Antimycobacterial Activity of Novel Theophylline-7-Acetic Acid Derivatives With Amino Acid Moieties.

    Stavrakov, Georgi; Valcheva, Violeta; Voynikov, Yulian; Philipova, Irena; Atanasova, Mariyana; Konstantinov, Spiro; Peikov, Plamen; Doytchinova, Irini

    2016-03-01

    The theophylline-7-acetic acid (7-TAA) scaffold is a promising novel lead compound for antimycobacterial activity. Here, we derive a model for antitubercular activity prediction based on 14 7-TAA derivatives with amino acid moieties and their methyl esters. The model is applied to a combinatorial library, consisting of 40 amino acid and methyl ester derivatives of 7-TAA. The best three predicted compounds are synthesized and tested against Mycobacterium tuberculosis H37Rv. All of them are stable, non-toxic against human cells and show antimycobacterial activity in the nanomolar range being 60 times more active than ethambutol. PMID:26502828

  12. DOTA-NOC, a high-affinity ligand of somatostatin receptor subtypes 2, 3 and 5 for labelling with various radiometals

    Earlier studies have shown that modification of the octapeptide octreotide in positions 3 and 8 may result in compounds with increased somatostatin receptor affinity that, if radiolabelled, display improved uptake in somatostatin receptor-positive tumours. The aim of a recent research study in our laboratory was to employ the parallel peptide synthesis approach by further exchanging the amino acid in position 3 of octreotide and coupling the macrocyclic chelator DOTA(1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to these peptides for labelling with radiometals like gallium-67 or -68, indium-111, yttrium-90 and lutetium-177. The purpose was to find radiopeptides with an improved somatostatin receptor binding profile in order to extend the spectrum of targeted tumours. A first peptide, [111In,90Y-DOTA]-1-Nal3-octreotide (111In,90Y-DOTA-NOC), was isolated which showed an improved profile. InIII-DOTA-NOC exhibited the following IC50 values (nM) when studied in competition with [125I][Leu8, d-Trp22, Tyr25]somatostatin-28 (values for YIII-DOTA-NOC are shown in parentheses): sstr2, 2.9±0.1 (3.3±0.2); sstr3, 8±2 (26±1.9); sstr5, 11.2±3.5 (10.4±1.6). Affinity towards sstr1 and 4 was very low or absent. InIII-DOTA-NOC is superior to all somatostatin-based radiopeptides having this particular type of binding profile, including DOTA-lanreotide, and has three to four times higher binding affinity to sstr2 than InIII,YIII-DOTA-Tyr3-octreotide (InIII,YIII-DOTA-TOC). In addition, [111In]DOTA-NOC showed a specific and high rate of internalization into AR4-2J rat pancreatic tumour cells which, after 4 h, was about two times higher than that of [111In]DOTA-TOC and three times higher than that of [111In]DOTA-octreotide ([111In]DOTA-OC). The internalized radiopeptides were externalized intact upon 2 h of internalization followed by an acid wash. After 2-3 h of externalization a plateau is reached, indicating a steady-state situation explained by reactivation of the

  13. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [177Lu-DOTA0,Tyr3]octreotate

    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [177Lu-DOTA0,Tyr3]octreotate. Male Lewis rats were injected with 278 or 555 MBq [177Lu-DOTA0,Tyr3]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of 99mTc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [177Lu-DOTA0,Tyr3]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [177Lu-DOTA0,Tyr3]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of 99mTc-DMSA SPECT scintigrams at 130 days after [177Lu-DOTA0,Tyr3]octreotate therapy correlated well with 1/creatinine (r 2 = 0.772, p 177Lu-DOTA0,Tyr3]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well as to maximise anti-tumour efficacy. (orig.)

  14. Synthesis and Antiviral Activity of Hydrogenated Ferulic Acid Derivatives

    Can Cui; Zhi-Peng Wang; Xiu-jiang Du; Li-Zhong Wang; Shu-Jing Yu; Xing-Hai Liu; Zheng-Ming Li; Wei-Guang Zhao

    2013-01-01

    A series of hydrogenated ferulic acid amide derivatives 4 were synthesized. The molecular structures of the synthesized compounds were analyzed by H1 NMR and HRMS. The biological activity study showed that some of them displayed excellent protection activity and curative activity against TMV at 500 μg/mL.

  15. Conformation of some carboxylic acids and their derivatives

    Kanters, J.A.; Kroon, Jan; Peerdeman, A.F.; Schoone, J.C.

    1967-01-01

    The conformation in the crystalline state of some aliphatic carboxylic acids and their derivatives has been analysed. This analysis, based upon the results of structure determinations by means of X-ray diffraction, seems to support the concept that the conformation of a molecule is governed chiefly

  16. Determination of peptide content and purity of DOTA-peptides by metal ion titration and UPLC. An alternative method to monitor quality of DOTA-peptides

    PRRT requires high specific activities, thus at low molar ratio between DOTA-peptide and radioactivity. Therefore, the ingredients of the reaction, including (radio)metals and DOTA-peptide must be pure and the content known. Our aim was to quantify content and purity of DOTA-peptide by a base-to-base separation of DOTA-peptide and metal-DOTA-peptide by UPLC and UV-detection. Quantification of these peaks reveals an accurate and sensitive method to quantify purity and content of DOTA-peptides. Moreover, this technique enables monitoring of the (radio)labeling process and co-introduction of impurities, including metal ions. (author)

  17. Single vial kit formulation for preparation of PET radiopharmaceutical. 68Ga-DOTA-TOC

    This paper describes the development of a lyophilized cold kit of DOTA-[Tyr3]-Octreotide (DOTA-TOC) for instant compounding of 68Ga-DOTA-TOC, suitable for diagnosis of neuroendocrine tumors. The work involved formulation of DOTA-TOC kits, optimization of radiolabeling, quality control of 68Ga-DOTA-TOC and animal biodistribution studies. The prepared kits enable a reliable method for preparation of 68Ga-DOTA-TOC of high radiochemical purity and excellent stability. Availability of such kits along with 68Ge/68Ga generators is expected to stimulate the widespread use of 68Ga-DOTA-TOC in nuclear medicine practice in developing countries. (author)

  18. Synthesis and complex forming property of phosphor acid derivatives

    Full text:With the aim to get new effective and selective extra gents of noble and non-ferrous metals from acid solution and industrial sewage, research of the dependence of 'structure effectiveness' the various phosphor acid derivatives with logical changeable structure (thio phosphor acids, derivatives of dialkoxythiophosphor, O-alkyl-methylphosphon, alkylphenylphosphon, diphenylphosphine acids also 4 methyl-1,3,2 dioxaphosphorinane) which contain different functional groups, the remains of heterocyclic amines and alkaloids, new derivatives of some analytical reagents were synthesized. The structure of synthesized compounds is approved by the results of IR-, PMR-, mass-spectrum analyze. Researching mass-spectrum decay of synthesized phosphor acid derivatives we defined that differing from O-dihexyl-S-propargyl-benzylthio phosphat, mass spectrum decay of O-dialkyl-S-(piperdynobutin-2-il)thio phosphat is characterized by the appearing [M-H]+ ions and during the decay ions with high intensiveness are formed. Fragmentation of M+ O-alkyl-O-(aminoalkyl)phenylphosphonate proceeds in various directions and characterized with the great number of phosphor containing ions, the possession of the second phenyl radical in the molecule of diphenylphosphon acid derivatives changes the fragmentation of molecular ion of diphenylphosphon acid derivatives. The process of extraction of noble (Au, Ag, Pt, Pd, Os) metals from hydrochloric-sulphur-nitrogen acid medium was analyzed by radioactive indicator's method. It was noticed that structure, strength, conformation of compounds, the temperature, of acid medium (0,1-10 M) and the nature of acids (HCL, H2SO4, HNO3) could have strong influence to the effectiveness of metal extraction. During the research of metals extraction from pure solutions we can see the followings: 1) There are such substances, which can be used as effective group reagent towards the Au, Ag and Pd. 2) Derivatives with acetylene extract ions of gold from medium of

  19. Yhteisöpalvelu Dota 2 -pelille

    Peltonen, Markus

    2014-01-01

    Opinnäytetyössä toteutettiin suomalaisille Dota 2 -pelin pelaajille tai pelistä kiin-nostuneille yhteisöportaali, josta voidaan seurata portaalin kautta käytyjen pelien tilastoja, järjestää pienimuotoisia turnauksia tai katsoa reaaliaikaista pelikuvaa käynnissä olevista peleistä tai pelialan tapahtumista. Tavoitteena oli laatia asiakkaan toiveiden mukainen yhteisöportaali, jota käyttäjän olisi myös helppo ylläpitää. Portaali toteutettiin Drupal 7 -sisällönhallintajärjestelmää käyttäen. Dr...

  20. Comparison of DOTA and NODAGA as chelators for 64Cu-labeled immunoconjugates

    Introduction: Bifunctional chelators have been shown to impact the biodistribution of monoclonal antibody (mAb)-based imaging agents. Recently, radiolabeled 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA)-peptide complexes have demonstrated improved in vivo stability and performance compared to their 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) counterparts. Here, we investigated if similar utility could be achieved with mAbs and compared 64Cu-labeled DOTA and NODAGA-immunoconjugates for the detection of epithelial cell adhesion molecule (EpCAM) in a prostate cancer model. Methods: DOTA and NODAGA-immunoconjugates of an EpCAM targeting mAb (mAb7) were synthesized and radiolabeled with 64Cu (DOTA: 40 °C for 1 hr; NODAGA: 25 °C for 1 hr). The average number of chelators per mAb was quantified by isotopic dilution, and the biological activity of the immunoconjugates was evaluated by flow cytometry and ELISA. Radioligand assays were performed to compare cellular uptake and determine the dissociation constant (Kd) and maximum number of binding sites (Bmax) for the immunoconjugates using DsRed-transfected PC3-cells. A PC3-DsRed xenograft tumor model was established in nude mice and used to perform biodistribution studies to compare organ uptake and pharmacokinetics. Results: 64Cu-DOTA-mAb7 and 64Cu-NODAGA-mAb7 were prepared with chelator/protein ratios of 2–3 and obtained in comparable radiochemical yields ranging from 59 to 71%. Similar immunoreactivity was observed with both agents, and mock labeling studies indicated that incubation at room temperature or 40 °C did not affect potency. 64Cu-NODAGA-mAb7 demonstrated higher in vitro cellular uptake while 64Cu-DOTA-mAb7 had higher Kd and Bmax values. From the biodistribution data, we found similar tumor uptake (13.44 ± 1.21%ID/g and 13.24 ± 4.86%ID/g for 64Cu-DOTA-mAb7 and 64Cu-NODAGA-mAb7, respectively) for both agents at 24 hr, although normal prostate tissue was significantly

  1. Amino acid decarboxylations produced by lipid-derived reactive carbonyls in amino acid mixtures.

    Hidalgo, Francisco J; León, M Mercedes; Zamora, Rosario

    2016-10-15

    The formation of 2-phenylethylamine and phenylacetaldehyde in mixtures of phenylalanine, a lipid oxidation product, and a second amino acid was studied to determine the role of the second amino acid in the degradation of phenylalanine produced by lipid-derived reactive carbonyls. The presence of the second amino acid usually increased the formation of the amine and reduced the formation of the Strecker aldehyde. The reasons for this behaviour seem to be related to the α-amino group and the other functional groups (mainly amino or similar groups) present in the side-chain of the amino acid. These groups are suggested to modify the lipid-derived reactive carbonyl but not the reaction mechanism because the Ea of formation of both 2-phenylethylamine and phenylacetaldehyde remained unchanged in all studied systems. All these results suggest that the amine/aldehyde ratio obtained by amino acid degradation can be modified by adding free amino acids during food formulation. PMID:27173560

  2. A comparison of 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging subcutaneous HER2-positive tumor xenografts in athymic mice using microSPECT/CT or microPET/CT

    Chan, Conrad; Scollard, Deborah A; McLarty, Kristin; Smith, Serena; Reilly, Raymond M

    2011-01-01

    Background Our objective was to compare 111In- or 64Cu-DOTA-trastuzumab Fab fragments for imaging small or large s.c. tumor xenografts in athymic mice that display a wide range of human epidermal growth factor receptor-2 (HER2) expression using microSPECT/CT or microPET/CT. Methods Trastuzumab Fab were labeled with 111In or 64Cu by conjugation to 1,4,7,10-tetraazacyclododecane N, N', N'', N'''-tetraacetic acid (DOTA). The purity of 111In- and 64Cu-DOTA-trastuzumab Fab was measured by SDS-PAGE...

  3. Copper(I) mediated cross-coupling of amino acid derived organozinc reagents with acid chlorides

    Hjelmgaard, Thomas; Tanner, David Ackland

    2006-01-01

    This paper describes the development of a straightforward experimental protocol for copper-mediated cross-coupling of amino acid derived beta-amido-alkylzinc iodides 1 and 3 with a range of acid chlorides. The present method uses CuCN center dot 2LiCl as the copper source and for organozinc reagent...

  4. 21 CFR 172.862 - Oleic acid derived from tall oil fatty acids.

    2010-04-01

    ... “Food Chemicals Codex.” 3d Ed. (1981), pp. 207-208, which is incorporated by reference, except that... 21 Food and Drugs 3 2010-04-01 2009-04-01 true Oleic acid derived from tall oil fatty acids. 172.862 Section 172.862 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND...

  5. Caldensinic acid, a benzoic acid derivative and others compounds from Piper carniconnectivum

    Alves, Harley da Silva; Souza, Maria de Fatima Vanderlei de; Chaves, Maria Celia de Oliveira, E-mail: cchaves@ltf.ufpb.b [Universidade Federal da Paraiba (UFPB), Joao Pessoa, PB (Brazil). Lab. de Tecnologia Farmaceutica

    2010-07-01

    A benzoic acid derivative - caldensinic acid, E-phythyl hexadecanoate, {beta}-sitosterol and stigmasterol mixture and phaeophytin a were isolated from the aerial parts of Piper carniconnectivum. The structures of these compounds were established unambiguously by IR, MS, 1D and 2D NMR analysis. (author)

  6. In Vitro Cytotoxicity of Low-Dose-Rate Radioimmunotherapy by the Alpha-Emitting Radioimmunoconjugate Thorium-227-DOTA-Rituximab

    Purpose: To determine whether the low-dose-rate α-particle-emitting radioimmunoconjugate 227Th-1,4,7,10-p-isothiocyanato-benzyl-tetraazacyclododecane-1,4,7, 10-tetraacetic acid (DOTA)-rituximab can be used to inactivate lymphoma cells growing as single cells and small colonies. Methods and Materials: CD20-positive lymphoma cell lines were treated with 227Th-DOTA-rituximab for 1-5 weeks. To simulate the in vivo situation with continuous but decreasing supply of radioimmunoconjugates from the blood pool, the cells were not washed after incubation with 227Th-DOTA-rituximab, but half of the medium was replaced with fresh medium, and cell concentration and cell-bound activity were determined every other day after start of incubation. A microdosimetric model was established to estimate the average number of hits in the nucleus for different localizations of activity. Results: There was a specific targeted effect on cell growth of the 227Th-DOTA-rituximab treatment. Although the cells were not washed after incubation with 227Th-DOTA-rituximab, the average contribution of activity in the medium to the mean dose was only 6%, whereas the average contribution from activity on the cells' own surface was 78%. The mean dose rates after incubation with 800 Bq/mL 227Th-DOTA-rituximab varied from 0.01 to 0.03 cGy/min. The average delay in growing from 105 to 107 cells/mL was 15 days when the cells were treated with a mean absorbed radiation dose of 2 Gy α-particle radiation from 227Th-DOTA-rituximab, whereas it was 11 days when the cells were irradiated with 6 Gy of X-radiation. The relative biologic effect of the treatment was estimated to be 2.9-3.4. Conclusions: The low-dose-rate radioimmunoconjugate 227Th-DOTA-rituximab is suitable for inactivation of single lymphoma cells and small colonies of lymphoma cells.

  7. Functionalization of a Triazine Dendrimer Presenting Four Maleimides on the Periphery and a DOTA Group at the Core.

    Lee, Changsuk; Ji, Kun; Simanek, Eric E

    2016-01-01

    A readily and rapidly accessible triazine dendrimer was manipulated in four steps with 23% overall yield to give a construct displaying four maleimide groups and DOTA. The maleimide groups of the dendrimer are sensitive to hydrolysis under basic conditions. The addition of up to four molecules of water can be observed via mass spectrometry and HPLC. The evolution in the alkene region of the ¹H-NMR--the transformation of the maleimide singlet to the appearance of two doublets--is consistent with imide hydrolysis and not the Michael addition. The hydrolysis events that proceeded over hours are sufficiently slower than the desired thiol addition reactions that occur in minutes. The addition of thiols to maleimides can be accomplished in a variety of solvents. The thiols examined derived from cysteine and include the protected amino acid, a protected dipeptide, and native oligopeptides containing either 9 or 18 amino acids. The addition reactions were monitored with HPLC and mass spectrometry in most cases. Complete substitution was observed for small molecule reactants. The model peptides containing nine or eighteen amino acids provided a mixture of products averaging between 3 and 4 substitutions/dendrimer. The functionalization of the chelate group with gadolinium was also accomplished easily. PMID:26978338

  8. Biological Activities of Oleanolic Acid Derivatives from Calendula officinalis Seeds.

    Zaki, Ahmed; Ashour, Ahmed; Mira, Amira; Kishikawa, Asuka; Nakagawa, Toshinori; Zhu, Qinchang; Shimizu, Kuniyoshi

    2016-05-01

    Phytochemical examination of butanol fraction of Calendula officinalis seeds led to the isolation of two compounds identified as 28-O-β-D-glucopyranosyl-oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS1) and oleanolic acid 3-O-β-D-glucopyranosyl (1→3)-β-D-glucopyranosiduronic acid (CS2). Biological evaluation was carried out for these two compounds such as melanin biosynthesis inhibitory, hyaluronic acid production activities, anti obesity using lipase inhibition and adipocyte differentiation as well as evaluation of the protective effect against hydrogen peroxide induced neurotoxicity in neuro-2A cells. The results showed that, compound CS2 has a melanin biosynthesis stimulatory activity; however, compound CS1 has a potent stimulatory effect for the production of hyaluronic acid on normal human dermal fibroblast from adult (NHDF-Ad). Both compounds did not show any inhibitory effect on both lipase and adipocyte differentiation. Compound CS2 could protect neuro-2A cells and increased cell viability against H2 O2 . These activities (melanin biosynthesis stimulatory and protective effect against H2 O2 of CS2 and hyaluronic acid productive activities of these triterpene derivatives) have been reported for the first time. Copyright © 2016 John Wiley & Sons, Ltd. PMID:26887328

  9. Development of radioinmunoconjugate 90Y-DOTA-nimotuzumab-Fab for therapy of EGFR over expressing tumors

    Many monoclonal antibodies conjugated with 1,4,7,10-tetraaza cyclododecane-N, N', N'', N'''-tetraacetic acid (DOTA) and radiolabeled with 90Y, have been used for radioimmunotherapy. As know IgG molecules are heavy proteins with a molecular weight of approximately 150 kDa. Accordingly, intact IgG antibodies may have significant slow kinetics biodistribution and severely limited properties of tissue penetration. Antibody fragments labeled with radio metals could be promising radiopharmaceuticals for imaging and non-invasive therapy due to its high affinity to the tumor, the lack of effector function and rapid pharmacokinetic. In this work, the nimotuzumab Fab fragment was obtained by cleavage with papain in molar excess. After separating the reaction mixture in three steps using affinity, size exclusion and ion exchange chromatography; the Fab fragment showed high values of purity, integrity and identity. The Fab fragment was derivatized with DOTA and labeled with 90Y. The radioimmunoconjugate with high radiochemical yield was assessed by in vitro stability with an excess of 50mM DTPA. The development of 90Y-DOTA-Nimotuzumab-Fab radioimmunoconjugate allows to count on as a potential agent for radioimmunotherapy. (Author)

  10. Development of [64Cu]-DOTA-anti-CD20 for targeted therapy

    Copper-64 was produced as a by-product of 55Co via 64Ni(p,n)64Cu by 15 MeV proton bombardment of natNi resulting in a thick target yield of 5.31 MBq/μAh (143.5 μCi/μAh) and a radiochemical separation yield of 95% (radionuclide purity >97% after 25 hours of bombardment). Rituximab was successively labeled with [64Cu]-CuCl2. N-succinimidyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-NHS) was prepared at 25 deg C using DOTA and N-hydroxy succinimide (NHS) in CH2Cl2 followed by the addition of 1 ml of a Rituximab pharmaceutical solution. Radiolabeling was performed at 37 deg C in 3 hours. Radio thin-layer chromatography showed an overall radiochemical purity of 90-95% at optimized conditions (specific activity=30 GBq/mg, labeling efficacy; 82%) using various chromatography systems. The final isotonic 64Cu- DOTA-Rituximab complex was passed through a 0.22 μm filter and checked by gel electrophoresis for radiolysis control. Stability of the final product was checked in the formulation and in presence of human serum at 37 deg C. (author)

  11. 177Lu-DOTA-lanreotide: a novel tracer as a targeted agent for tumor therapy

    177Lu of specific activity ∼100-110 TBq/g and radionuclidic purity of ∼100% was obtained by irradiation of enriched Lu2O3 (60.6% 176Lu) target for 7 days at a thermal neutron flux of 3x1013n/cm2/sec. The 177Lu labeling of a macrocyclic bifunctional chelating agent viz. 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) has been extensively studied. Lanreotide, [β-naphthyl-Ala-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2] a disulfide-linked cyclic octapeptide and a somatostatin analog, reported to bind with a wide variety of tumors expressing somatostatin receptors, was conjugated with DOTA. The peptide-BFCA conjugate was characterized with the help of high-resolution two-dimensional proton NMR spectroscopy. The 177Lu labeling of the DOTA-lanreotide conjugate has been standardized to give a radiolabeling yield of 85%. The tracer showed specific binding with A-431 human epidermoid carcinoma and IMR-32 human brain neuroblastoma cells

  12. TmDOTA-tetraglycinate encapsulated liposomes as pH-sensitive LipoCEST agents.

    Ana Christina L Opina

    Full Text Available Lanthanide DOTA-tetraglycinate (LnDOTA-(gly₄⁻ complexes contain four magnetically equivalent amide protons that exchange with protons of bulk water. The rate of this base catalyzed exchange process has been measured using chemical exchange saturation transfer (CEST NMR techniques as a function of solution pH for various paramagnetic LnDOTA-(gly₄⁻ complexes to evaluate the effects of lanthanide ion size on this process. Complexes with Tb(III, Dy(III, Tm(III and Yb(III were chosen because these ions induce large hyperfine shifts in all ligand protons, including the exchanging amide protons. The magnitude of the amide proton CEST exchange signal differed for the four paramagnetic complexes in order, Yb>Tm>Tb>Dy. Although the Dy(III complex showed the largest hyperfine shift as expected, the combination of favorable chemical shift and amide proton CEST linewidth in the Tm(III complex was deemed most favorable for future in vivo applications where tissue magnetization effects can interfere. TmDOTA-(gly₄⁻ at various concentrations was encapsulated in the core interior of liposomes to yield lipoCEST particles for molecular imaging. The resulting nanoparticles showed less than 1% leakage of the agent from the interior over a range of temperatures and pH. The pH versus amide proton CEST curves differed for the free versus encapsulated agents over the acidic pH regions, consistent with a lower proton permeability across the liposomal bilayer for the encapsulated agent. Nevertheless, the resulting lipoCEST nanoparticles amplify the CEST sensitivity by a factor of ∼10⁴ compared to the free, un-encapsulated agent. Such pH sensitive nano-probes could prove useful for pH mapping of liposomes targeted to tumors.

  13. [Cardioprotective properties of new glutamic acid derivative under stress conditions].

    Perfilova, V N; Sadikova, N V; Berestovitskaia, V M; Vasil'eva, O S

    2014-01-01

    The effect of new glutamic acid derivative on the cardiac ino- and chronotropic functions has been studied in experiments on rats exposed to 24-hour immobilization-and-pain stress. It is established that glutamic acid derivative RGPU-238 (glufimet) at a dose of 28.7 mg/kg increases the increment of myocardial contractility and relaxation rates and left ventricular pressure in stress-tested animals by 13 1,1, 72.4, and 118.6%, respectively, as compared to the control group during the test for adrenoreactivity. Compound RGPU-238 increases the increment of the maximum intensity of myocardium functioning by 196.5 % at 30 sec of isometric workload as compared to the control group. The cardioprotective effect of compound RGPU-238 is 1.5 - 2 times higher than that of the reference drug phenibut. PMID:25365864

  14. Anacardic acid derivatives from Brazilian propolis and their antibacterial activity

    Silva, M.S.S.; Lima, S.G. de; Lopes, J.A.D.; Chaves, M.H.; Cito, A.M.G.L. [Universidade Federal do Piaui (UFPI), Teresina, PI (Brazil). Dept. de Quimica]. E-mail: gracito@ufpi.br; Oliveira, E.H. [Universidade Federal do Piaui (UFPI), Teresina, PI (Brazil). Dept. de Microbiologia e Parasitologia; Reis, F.A.M. [Universidade Estadual de Campinas (UNICAMP), Campinas, SP (Brazil). Inst. de Quimica

    2008-07-01

    Propolis is a sticky, gummy, resinous substance collected by honeybees (Apis mellifera L.) from various plant sources, which has excellent medicinal properties. This paper describes the isolation and identification of triterpenoids and anacardic acid derivatives from Brazilian propolis and their antibacterial activity. Their structures were elucidated by {sup 1}H and {sup 13}C NMR, including uni- and bidimensional techniques; in addition, comparisons were made with data from academic literature. These compounds were identified as: cardanols (1a + 1b), cardols (2a + 2b), mono ene anacardic acid (3), alpha-amirine (4), beta-amirine (5), cycloartenol (6), 24-methylene-cycloartenol (7) and lupeol (8). The determination of the position of the double bond after a reaction with Dimethyl disulfide (DMDS) is described for the phenol derivatives. The ethanolic extract was tested in vitro for antimicrobial activity by using the disc diffusion method and it showed significant results against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Shigella spp. (author)

  15. Anacardic acid derivatives from Brazilian propolis and their antibacterial activity

    Propolis is a sticky, gummy, resinous substance collected by honeybees (Apis mellifera L.) from various plant sources, which has excellent medicinal properties. This paper describes the isolation and identification of triterpenoids and anacardic acid derivatives from Brazilian propolis and their antibacterial activity. Their structures were elucidated by 1H and 13C NMR, including uni- and bidimensional techniques; in addition, comparisons were made with data from academic literature. These compounds were identified as: cardanols (1a + 1b), cardols (2a + 2b), mono ene anacardic acid (3), alpha-amirine (4), beta-amirine (5), cycloartenol (6), 24-methylene-cycloartenol (7) and lupeol (8). The determination of the position of the double bond after a reaction with Dimethyl disulfide (DMDS) is described for the phenol derivatives. The ethanolic extract was tested in vitro for antimicrobial activity by using the disc diffusion method and it showed significant results against Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa and Shigella spp. (author)

  16. Ionic products of metal complexes with dithiocarbonic acid derivatives

    Ionic products of the complexes of certain sulfide-forming metal ions (In, Cd, Te, etc.) with alkyl derivates of dithiocarbonic acid have been defined. The possibility to use ionic products of alkyl xanthates for predicting the practicability of employing alkyl xanthates as analytic reagents in titrimetric methods of analysis, in extractional methods of separation and determination of elements, increase in the determination selectivity, is shown. 11 refs., 1 fig., 1 tab

  17. Branched-chain 2-keto acid decarboxylases derived from Psychrobacter.

    Wei, Jiashi; Timler, Jacobe G; Knutson, Carolann M; Barney, Brett M

    2013-09-01

    The conversion of branched-chain amino acids to branched-chain acids or alcohols is an important aspect of flavor in the food industry and is dependent on the Ehrlich pathway found in certain lactic acid bacteria. A key enzyme in the pathway, the 2-keto acid decarboxylase (KDC), is also of interest in biotechnology applications to produce small branched-chain alcohols that might serve as improved biofuels or other commodity feedstocks. This enzyme has been extensively studied in the model bacterium Lactococcus lactis, but is also found in other bacteria and higher organisms. In this report, distinct homologs of the L. lactis KDC originally annotated as pyruvate decarboxylases from Psychrobacter cryohalolentis K5 and P. arcticus 273-4 were cloned and characterized, confirming a related activity toward specific branched-chain 2-keto acids derived from branched-chain amino acids. Further, KDC activity was confirmed in intact cells and cell-free extracts of P. cryohalolentis K5 grown on both rich and defined media, indicating that the Ehrlich pathway may also be utilized in some psychrotrophs and psychrophiles. A comparison of the similarities and differences in the P. cryohalolentis K5 and P. arcticus 273-4 KDC activities to other bacterial KDCs is presented. PMID:23826991

  18. Quantification of Acidic Compounds in Complex Biomass-Derived Streams

    Karp, Eric M.; Nimlos, Claire T.; Deutch, Steve; Salvachua, Davinia; Cywar, Robin M.; Beckham, Gregg T.

    2016-09-07

    Biomass-derived streams that contain acidic compounds from the degradation of lignin and polysaccharides (e.g. black liquor, pyrolysis oil, pyrolytic lignin, etc.) are chemically complex solutions prone to instability and degradation during analysis, making quantification of compounds within them challenging. Here we present a robust analytical method to quantify acidic compounds in complex biomass-derived mixtures using ion exchange, sample reconstitution in pyridine and derivatization with BSTFA. The procedure is based on an earlier method originally reported for kraft black liquors and, in this work, is applied to identify and quantify a large slate of acidic compounds in corn stover derived alkaline pretreatment liquor (APL) as a function of pretreatment severity. Analysis of the samples is conducted with GCxGC-TOFMS to achieve good resolution of the components within the complex mixture. The results reveal the dominant low molecular weight components and their concentrations as a function of pretreatment severity. Application of this method is also demonstrated in the context of lignin conversion technologies by applying it to track the microbial conversion of an APL substrate. Here too excellent results are achieved, and the appearance and disappearance of compounds is observed in agreement with the known metabolic pathways of two bacteria, indicating the sample integrity was maintained throughout analysis. Finally, it is shown that this method applies more generally to lignin-rich materials by demonstrating its usefulness in analysis of pyrolysis oil and pyrolytic lignin.

  19. Optimization of Time-Resolved Fluorescence Assay for Detection of Eu-DOTA-labeled Ligand-Receptor Interactions

    De Silva, Channa R.; Vagner, Josef; Lynch, Ronald; Gillies, Robert J.; Hruby, Victor J.

    2009-01-01

    Lanthanide-based luminescent ligand binding assays are superior to traditional radiolabel assays due to improved sensitivity and affordability in high throughput screening while eliminating the use of radioactivity. Despite significant progress using lanthanide(III)-coordinated chelators such as DTPA derivatives, dissociation-enhanced lanthanide fluoroimmunoassays (DELFIA) have not yet been successfully used with more stable chelators, e.g. DOTA derivatives, due to the incomplete release of l...

  20. Tumor targeting using 67Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: 67Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (67Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel 67Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [68Ga]-gallium radionuclide.

  1. Preparation & in vitro evaluation of 90 Y-DOTA-rituximab

    Mythili Kameswaran

    2016-01-01

    Full Text Available Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL. Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA to rituximab, its radiolabelling with [90] Y and in vitro and in vivo evaluation to determine its potential as a radioimmunotherapeutic agent. Methods: Rituximab was conjugated with p-SCN-Bn-DOTA at 1:1 antibody: DOTA molar ratio. The number of DOTA molecules linked to one molecule of rituximab was determined by radioassay and spectroscopic assay. Radiolabelling of rituximab with 90 Y was carried out and its in vitro stability was evaluated. In vitro cell binding studies were carried out in Raji cells expressing CD20 antigen. Biodistribution studies were carried out in normal Swiss mice. Results: Using both radioassay and spectroscopic method, it was determined that about five molecules of DOTA were linked to rituximab. Radiolabelling of the rituximab conjugate with [90] Y and subsequent purification on PD-10 column gave a product with radiochemical purity (RCP > 98 per cent which was retained at > 90 per cent up to 72 h when stored at 37°C. In vitro cell binding experiments of 90 Y-DOTA-rituximab with Raji cells exhibited specific binding of 20.7 ± 0.1 per cent with [90] Y-DOTA-rituximab which reduced to 15.5 ± 0.2 per cent when incubated with cold rituximab. The equilibrium constant K d for 90 Y-DOTA-Rituximab was determined to be 3.38 nM. Radiolabelled antibody showed clearance via hepatobiliary and renal routes and activity in tibia was found to be quite low indicating in vivo stability of [90] Y-DOTA-rituximab. Interpretation & conclusions: p-SCN-Bn-DOTA was conjugated with rituximab and radiolabelling with 90 Y was

  2. Gd-DOTA in musculoskeletal diseases

    T1-weighted images after the injection of Gd-DOTA, a new paramagnetic contrast medium, were compared with non-enhanced T2-weighted images in 42 consecutive cases of musculoskeletal pathology. In addition we evaluated the incidence of side effects. Enhanced T1-weighted images were superior in depicting the various parts of a lesion and the borders between the lesion and normal tissue or perifocal reaction. On the other hand the non-enhanced T2-weighted images better depicted the border between the perifocal reaction and normal tissue. In aggressive lesions, especially in malignant tumours, the two sequences are complementary. Enhanced T1-weighted images did not contribute significantly to assessing benign lesions. The incidence of side effects was acceptable and no severe reactions occurred. (orig.)

  3. Injectable hydrogels derived from phosphorylated alginic acid calcium complexes

    Phosphorylation of sodium alginate salt (NaAlg) was carried out using H3PO4/P2O5/Et3PO4 followed by acid–base reaction with Ca(OAc)2 to give phosphorylated alginic acid calcium complexes (CaPAlg), as a water dispersible alginic acid derivative. The modified alginate derivatives including phosphorylated alginic acid (PAlg) and CaPAlg were characterized by nuclear magnetic resonance spectroscopy for 1H, and 31P nuclei, high resolution inductively coupled plasma optical emission spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. CaPAlg hydrogels were prepared simply by mixing CaPAlg solution (2 w/v%) with NaAlg solution (2 w/v%) in various ratios (2:8, 4:6, 6:4, 8:2) of volume. No additional calcium salts such as CaSO4 or CaCl2 were added externally. The gelation was completed within about 3–40 min indicating a high potential of hydrogel delivery by injection in vivo. Their mechanical properties were tested to be ≤ 6.7 kPa for compressive strength at break and about 8.4 kPa/mm for elastic modulus. SEM analysis of the CaPAlg hydrogels showed highly porous morphology with interconnected pores of width in the range of 100–800 μm. Cell culture results showed that the injectable hydrogels exhibited comparable properties to the pure alginate hydrogel in terms of cytotoxicity and 3D encapsulation of cells for a short time period. The developed injectable hydrogels showed suitable physicochemical and mechanical properties for injection in vivo, and could therefore be beneficial for the field of soft tissue engineering. - Highlights: • Preparation of water-soluble alginic acid complexes with calcium phosphate • Self-assembly of the phosphorylated alginic acid calcium complexes with sodium alginate • Preparation of injectable hydrogels with diverse gelation times within about 3–40 min

  4. Biarylalkyl Carboxylic Acid Derivatives as Novel Antischistosomal Agents.

    Mäder, Patrick; Blohm, Ariane S; Quack, Thomas; Lange-Grünweller, Kerstin; Grünweller, Arnold; Hartmann, Roland K; Grevelding, Christoph G; Schlitzer, Martin

    2016-07-01

    Parasitic platyhelminths are responsible for serious infectious diseases, such as schistosomiasis, which affect humans as well as animals across vast regions of the world. The drug arsenal available for the treatment of these diseases is limited; for example, praziquantel is the only drug currently used to treat ≥240 million people each year infected with Schistosoma spp., and there is justified concern about the emergence of drug resistance. In this study, we screened biarylalkyl carboxylic acid derivatives for their antischistosomal activity against S. mansoni. These compounds showed significant influence on egg production, pairing stability, and vitality. Tegumental lesions or gut dilatation was also observed. Substitution of the terminal phenyl residue in the biaryl scaffold with a 3-hydroxy moiety and derivatization of the terminal carboxylic acid scaffold with carboxamides yielded compounds that displayed significant antischistosomal activity at concentrations as low as 10 μm with satisfying cytotoxicity values. The present study provides detailed insight into the structure-activity relationships of biarylalkyl carboxylic acid derivatives and thereby paves the way for a new drug-hit moiety for fighting schistosomiasis. PMID:27159334

  5. Comparison of 90Y/177Lu labeled DOTA-Bz-RGD tetramer and DOTA-RGD tetramer

    90Y/177Lu labeled DOTA-Bz-RGD tetramer and DOTA-RGD tetramer were prepared, and the effect of Bz-DOTA and DOTA on labeling conditions and in vitro stability of radiolabeled compounds was compared. The labeling conditions, including reaction pH, reaction temperature and reaction time, were investigated. ITLC and HPLC show that the labeling yields of four radiolabeled compounds are more than 95% under optimal conditions (pH=6.0, reacting at 100 degree C for 15-20 min); the four radiolabeled compounds show pretty good stability in saline and fetal bovine serum. Although introducing of Bz has no effect on labeling conditions and in vitro stability of radiolabeled compounds, it brings a little change on molecule polarity. HPLC analysis and lg P values reveal that introducing of Bz increases the lipophilicity of radiolabeled compounds. (authors)

  6. Dosimetric Studies in Normal Mice of 177Lu-DOTA-SP and 177Lu-DOTA-His2-MG

    DOTA-Substance-P (SP) and DOTA-minigastrin (His2-MG) labeled with 177Lu could be used in peptide receptor radionuclide therapy (PRRT) for treatment of various tumour species. Biodistribution studies of both radiopharmaceuticals in normal mice were performed at different times. Absorbed doses in mouse organs were estimated and extrapolated to humans. Dosimetric calculations showed that kidneys received the highest dose, for both radiopharmaceuticals. The Maximum Tolerated Activity (MTA) of 177Lu-DOTA-SP that can be administered without kidney toxicity are 414 and 422 MBq/kg for the standard adult man and woman, respectively. In the same way, the MTA of 177Lu-DOTA-His2-MG are 488 and 518 MBq/kg for the standard adult man and woman, respectively. (authors)

  7. Comparison of [177Lu-DOTA0,Tyr3]octreotate and [177Lu-DOTA0,Tyr3]octreotide: which peptide is preferable for PRRT?

    Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [177Lu-DOTA0,Tyr3]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [177Lu-DOTA0,Tyr3]octreotide (177Lu-DOTATOC) and [177Lu-DOTA0,Tyr3]octreotate (177Lu-DOTATATE), to see which peptide should be preferred for PRRT with 177Lu. In the same patients, 3,700 MBq 177Lu-DOTATOC and 3,700 MBq 177Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys. All patients had longer residence times in spleen, kidneys and tumours after use of 177Lu-DOTATATE (p=0.016 in each case). Comparing 177Lu-DOTATATE with 177Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using 177Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after 177Lu-DOTATATE was comparable to that after 177Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for 177Lu-DOTATOC. 177Lu-DOTATATE had a longer tumour residence time than 177Lu-DOTATOC. Despite a longer residence time in kidneys after 177Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate. (orig.)

  8. Synthesis of some bis- and mono-2-hydroxybenzoic acid derivatives and the determination of their acidity constants

    KATARINA M. PENOV GASI; MIRJANA M. POPSAVIN; GYONGYI GY. VASTAG; TEREZIA M. SURANYI; Djurendic, Evgenija A.

    2000-01-01

    Several bis- and mono-2-hydroxybenzoic acid derivatives were synthesized by the reaction of methyl 2-hydroxybenzoate with some alcohols (diols, polyols and amino alcohols) and their acidity constants were determined in 60 % aqueous ethanol by the potentiometric titration method. It has been shown that the biochemical behaviour of these compounds is greatly dependent on their acidity. It appears that the ester derivatives are weaker acids than the amide derivatives and, therefore, can be poten...

  9. SPECT/CT of lung nodules using 111In-DOTA-c(RGDfK) in a mouse lung carcinogenesis model

    Lung cancer is one of the leading causes of cancer-related deaths worldwide, including Japan. Although computed tomography (CT) can detect small lung lesions such as those appearing as ground glass opacity, it cannot differentiate between malignant and non-malignant lesions. Previously, we have shown that single photon emission computed tomography (SPECT) imaging using 111In-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo-(Arg-Gly-Asp-D-Phe-Lys) (DOTA-c(RGDfK)), an imaging probe of αvβ3 integrin, is useful for the early detection of pancreatic cancer in a hamster pancreatic carcinogenesis model. In this study, we aimed to assess the usefulness of SPECT/CT with 111In-DOTA-c(RGDfK) for the evaluation of the malignancy of lung cancer. Lung tumors were induced by a single intraperitoneal injection (250 mg/kg) of urethane in male A/J mice. Twenty-six weeks after the urethane treatment, SPECT was performed an hour after injection of 111In-DOTA-c(RGDfK). Following this, the radioactivity ratios of tumor to normal lung tissue were measured by autoradiography (ARG) in the excised lung samples. We also examined the expression of αvβ3 integrin in mouse and human lung samples. Urethane treatment induced 5 hyperplasias, 41 adenomas and 12 adenocarcinomas in the lungs of 8 A/J mice. SPECT with 111In-DOTA-c(RGDfK) could clearly visualize lung nodules, though we failed to detect small lung nodules like adenoma and hyperplasias (adenocarcinoma: 66.7%, adenoma: 33.6%, hyperplasia: 0.0%). ARG analysis revealed significant uptake of 111In-DOTA-c(RGDfK) in all the lesions. Moreover, tumor to normal lung tissue ratios increased along with the progression of carcinogenesis. Histopathological examination using human lung tissue samples revealed clear up-regulation of αvβ3 integrin in well-differentiated adenocarcinoma (Noguchi type B and C) rather than atypical adenomatous hyperplasia. Although there are some limitations in evaluating the malignancy of small lung

  10. A novel polymeric herbicide based on phenoxyacetic acid derivatives

    Wimol Klaichim

    2009-01-01

    Full Text Available A novel polymeric herbicide based on phenoxyacetic acid derivatives was prepared by the reaction of epoxidised liquid natural rubber (ELNR with 2,4-dichlorophenoxyacetic acid (2,4-D or 2-methyl-4-chlorophenoxyacetic acid(MCPA. The liquid natural rubber (LNR was firstly obtained from the degradation of natural rubber latex with tert-butyl hydroperoxide and cobalt acetylacetonate at 65oC for 72 hrs. The epoxidised liquid natural rubber was prepared from thereaction of LNR with formic acid and hydrogen peroxide at 50oC for 6 hrs. The reaction of epoxidised liquid natural rubber with 2,4-D or MCPA using triethylamine as a catalyst in toluene was performed at 70, 80, and 90oC for 6, 9, 12, 18, and 24hrs. The polymeric herbicides obtained were characterized and the grafting percentage of 2,4-D or MCPA onto liquid natural rubber were also determined by FT-IR and 1H-NMR spectroscopy. It was found that the grafting percentage increased with increasing amount of reactants, temperature, and reaction time. The release of 2,4-D and MCPA from polymeric herbicides was investigated in pH 6, 7, and 8 buffers at room temperature. The results show that the slowest release of 2,4-D and MCPA was found to be constant at pH 7 for 14 and 10 days, respectively.

  11. Novel sustainable polymers derived from renewable rosin and fatty acids

    Wilbon, Perry

    In the work of this dissertation, polymers derived from renewable bio-based resources prepared by various polymerization techniques were investigated. The properties of these polymeric materials were characterized and discussed. Rosin was first converted into acrylate or methacrylate monomers for atom transfer radical polymerization (ATRP). Second, rosin was combined with vegetable oil to produce completely renewable novel polyesters by acyclic diene metathesis (ADMET) polymerization. Third, degradable block copolymers were synthesized composed of polycaprolactone and rosin grafted polycaprolactone with the aid of ring-opening polymerization (ROP). Finally, degradable polyesters were produced using vegetable oil derivatives as starting materials. These new rosin and fatty acid based renewable polymer materials will have potential applications as sustainable thermoplastics, thermoplastic elastomers, etc.

  12. Quinic acid derivatives inhibit dengue virus replication in vitro

    Zanello, Paula Rodrigues; Koishi, Andrea Cristine; Rezende Júnior, Celso de Oliveira; Oliveira, Larissa Albuquerque; Pereira, Adriane Antonia; de Almeida, Mauro Vieira; Duarte dos Santos, Claudia Nunes; Bordignon, Juliano

    2015-01-01

    Background Dengue is the most prevalent arboviral disease in tropical and sub-tropical areas of the world. The incidence of infection is estimated to be 390 million cases and 25,000 deaths per year. Despite these numbers, neither a specific treatment nor a preventive vaccine is available to protect people living in areas of high risk. Results With the aim of seeking a treatment that can mitigate dengue infection, we demonstrated that the quinic acid derivatives known as compound 2 and compoun...

  13. Banana-shaped molecules derived from substituted isophthalic acids

    H T Nguyen; J P Bedel; J C Rouillon; J P Marcerou; M F Achard

    2003-08-01

    In this paper we present a review of five-rings banana-shaped molecules derived from isophthalic acids. This study deals with about a hundred compounds and most of them have not been published. By a combination of several linking groups and different selected substituents either on the outer rings or on the central core, several mesophases with switching properties are induced. The study of homologous series underlines the importance of the length and nature of the terminal chains. X-ray analysis reveals several new structures.

  14. Antioxidant and cytotoxic activity of mono- and bissalicylic acid derivatives

    Đurendić Evgenija A.; Savić Marina P.; Jovanović-Šanta Suzana S.; Sakač Marija N.; Kojić Vesna V.; Szécsi Mihály; Oklješa Aleksandar M.; Poša Mihalj M.; Penov-Gaši Katarina M.

    2014-01-01

    A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the transesterification of methyl salicylate (methyl 2-hydroxybenzoate) with 3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol, 3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in alkaline conditions is reported. All compounds were tested in vitro on three malignant cell lines (MCF-7, MDA-MB-231, PC-3) and one non-tumor cell line (MRC- 5). Strong cytotoxicity agains...

  15. radiolabeling of DOTA-substance P with 177Lu and biodistribution of 177Lu-DOTA-substance P

    The aim of this project is to evaluate the biodistribution of 177Lu-DOTA-SP in normal mice and in PANC-1 tumor bearing nude mice and to pave the way for its potentially medical application. In this study, 177Lu-DOTA-SP was successfully prepared with labeling yield of greater than 90% at optimized conditions and more than 98% of radiochemical purity after C18 Sep-Pak purification. 177Lu-DOTA-SP showed good stability in saline and in 5% serum while it decomposed slowly in 10% serum. Biodistribution studies in normal mice showed high uptake of 177Lu-DOTA-SP in the kidneys, indicating the excretion mainly by renal pathway. In addition, 177Lu-DOTA-SP was washed out from the blood quickly. Bio- distribution of 177Lu-DOTA-SP in PANC-1 tumor bearing mice showed higher uptake in pancreatic tumor than that in normal pancreas, indicating the presence of NK-1 receptors in PANC-1 pancreatic tumor. However, from SPECT image, no radioactivity accumulation was observed in PANC-1 tumor. Further evaluation is needed to confirm its potential application for radiotherapy of pancreatic cancers. (authors)

  16. Efficient Debromination of Vicinal (, (-Dibromo Carboxylic Acid Derivatives with the Sm/HOAc System

    2002-01-01

    The α, β vicinal dibromo carboxylic acid and its derivatives were debrominated with Sm/HOAc system to afford the corresponding cinnamic acid and its derivatives in good yields under mild conditions.

  17. Cinnamic Acid and Its Derivatives Inhibit Fructose-Mediated Protein Glycation

    Sirintorn Yibchok-anun; Sirichai Adisakwattana; Weerachat Sompong; Sathaporn Ngamukote; Aramsri Meeprom

    2012-01-01

    Cinnamic acid and its derivatives have shown a variety of pharmacologic properties. However, little is known about the antiglycation properties of cinnamic acid and its derivatives. The present study sought to characterize the protein glycation inhibitory activity of cinnamic acid and its derivatives in a bovine serum albumin (BSA)/fructose system. The results demonstrated that cinnamic acid and its derivatives significantly inhibited the formation of advanced glycation end products (AGEs) by...

  18. 64Cu-DOTA-trastuzumab PET imaging and HER2 specificity of brain metastases in HER2-positive breast cancer patients

    Kurihara, Hiroaki; Hamada, Akinobu; Yoshida, Masayuki; Shimma, Schuichi; Hashimoto, Jun; YONEMORI, KAN; Tani, Hitomi; Miyakita, Yasuji; Kanayama, Yousuke; Wada, Yasuhiro; Kodaira, Makoto; Yunokawa, Mayu; Yamamoto, Harukaze; Shimizu, Chikako; Takahashi, Kazuhiro

    2015-01-01

    Background The purpose of this study was to determine whether brain metastases from HER2-positive breast cancer could be detected noninvasively using positron emission tomography (PET) with 64Cu-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-trastuzumab. Methods PET was performed on five patients with brain metastases from HER2-positive breast cancer, at 24 or 48 h after the injection of approximately 130 MBq of the probe 64Cu-DOTA-trastuzumab. Radioactivity in metastatic bra...

  19. Synthesis and antimicrobial activities of new higher amino acid Schiff base derivatives of 6-aminopenicillanic acid and 7-aminocephalosporanic acid

    Özdemir (nee Güngör), Özlem; Gürkan, Perihan; Özçelik, Berrin; Oyardı, Özlem

    2016-02-01

    Novel β-lactam derivatives (1c-3c) (1d-3d) were produced by using 6-aminopenicillanic acid (6-APA), 7-aminocephalosporanic acid (7-ACA) and the higher amino acid Schiff bases. The synthesized compounds were characterized by elemental analysis, IR, 1H/13C NMR and UV-vis spectra. Antibacterial activities of all the higher amino acid Schiff bases (1a-3a) (1b-3b) and β-lactam derivatives were screened against three gram negative bacteria (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 27853, Acinetobacter baumannii RSKK 02026), three gram positive bacteria (Staphylococcus aureus ATCC 25923, Enterococcus faecalis ATCC 07005, Bacillus subtilis ATCC 6633) and their drug-resistant isolates by using broth microdilution method. Two fungi (Candida albicans and Candida krusei) were used for antifungal activity.

  20. Geometrical confinement of Gd(DOTA) molecules within mesoporous silicon nanoconstructs for MR imaging of cancer

    Gizzatov, Ayrat; Stigliano, Cinzia; Ananta, Jeyerama S.; Sethi, Richa; Xu, Rong; Guven, Adem; Ramirez, Maricela; Shen, Haifa; Sood, Anil; Ferrari, Mauro; Wilson, Lon J.; Liu, Xuewu; Decuzzi, Paolo

    2014-01-01

    Porous silicon has been used for the delivery of therapeutic and imaging agents in several biomedical applications. Here, mesoporous silicon nanoconstructs (SiMPs) with a discoidal shape and a sub-micrometer size (1,000 × 400 nm) have been conjugated with gadolinium-tetraazacyclododecane tetraacetic acid Gd(DOTA) molecules and proposed as contrast agents for Magnetic Resonance Imaging. The surface of the SiMPs with different porosities – small pore (SP: ~ 5 nm) and huge pore (HP: ~ 40 nm) – a...

  1. Synthesis and anticancer activity of novel fluorinated asiatic acid derivatives.

    Gonçalves, Bruno M F; Salvador, Jorge A R; Marín, Silvia; Cascante, Marta

    2016-05-23

    A series of novel fluorinated Asiatic Acid (AA) derivatives were successfully synthesized, tested for their antiproliferative activity against HeLa and HT-29 cell lines, and their structure activity relationships were evaluated. The great majority of fluorinated derivatives showed stronger antiproliferative activity than AA in a concentration dependent manner. The most active compounds have a pentameric A-ring containing an α,β-unsaturated carbonyl group. The compounds with better cytotoxic activity were then evaluated against MCF-7, Jurkat, PC-3, A375, MIA PaCa-2 and BJ cell lines. Derivative 14 proved to be the most active compound among all tested derivatives and its mechanism of action was further investigated in HeLa cell line. The results showed that compound 14 induced cell cycle arrest in G0/G1 stage as a consequence of up-regulation of p21(cip1/waf1) and p27(kip1) and down-regulation of cyclin D3 and Cyclin E. Furthermore, compound 14 was found to induce caspase driven-apoptosis with activation of caspases-8 and caspase-3 and the cleavage of PARP. The cleavage of Bid into t-Bid, the up-regulation of Bax and the down-regulation of Bcl-2 were also observed after treatment of HeLa cells with compound 14. Taken together, these mechanistic studies revealed the involvement of extrinsic and intrinsic pathways in the apoptotic process induced by compound 14. Importantly, the antiproliferative activity of this compound on the non-tumor BJ human fibroblast cell line is weaker than in the tested cancer cell lines. The enhanced potency (between 45 and 90-fold more active than AA in a panel of cancer cell lines) and selectivity of this new AA derivative warrant further preclinical evaluation. PMID:26974379

  2. 68Ga- and 111In-labelled DOTA-RGD peptides for imaging of αvβ3 integrin expression

    αvβ3 integrins are important cell adhesion receptors involved in angiogenic processes. Recently, we demonstrated using [18F]Galacto-RGD that monitoring of αvβ3 expression is feasible. Here, we introduce 68Ga- and 111In-labelled derivatives and compare them with [18F]Galacto-RGD. For radiolabelling, cyclo(RGDfK(DOTA)) was synthesised using SPPS. For in vitro characterisation determination of partition coefficients, protein binding, metabolic stability, αvβ3 affinity and cell uptake and for in vivo characterization, biodistribution studies and micro positron emission tomography (PET) imaging were carried out. For in vivo and in vitro studies, human melanoma M21 (αvβ3 positive) and M21-L (αvβ3 negative) cells were used. Both tracers can be synthesised straightforward. The compounds showed hydrophilic properties and high metabolic stability. Up to 23% protein-bound activity for [68Ga]DOTA-RGD and only up to 1.4% for [111In]DOTA-RGD was found. Cell uptake studies indicate receptor-specific accumulation. This is confirmed by the biodistribution data. One hour p.i. accumulation in αvβ3-positive tumours was 2.9 ± 0.3%ID/g and in αvβ3-negative tumours 0.8 ± 0.1%ID/g for [68Ga]DOTA-RGD ([111In]DOTA-RGD: 1.9 ± 0.3%ID/g and 0.5 ± 0.2%ID/g; [18F]Galacto-RGD: 1.6 ± 0.2%ID/g and 0.4 ± 0.1%ID/g). Thus, tumour uptake ratios were comparable. Due to approx. 3-fold higher blood pool activities for [68Ga]DOTA-RGD, tumour/blood ratios were higher for [111In]DOTA-RGD and [18F]Galacto-RGD. However, microPET studies demonstrated that visualisation of αvβ3-positive tumours using [68Ga]DOTA-RGD is possible. Our data indicate that [68Ga]DOTA-RGD allows monitoring of αvβ3 expression. Especially, the much easier radiosynthesis compared to [18F]Galacto-RGD would make it an attractive alternative. However, due to higher blood pool activity, [18F]Galacto-RGD remains superior for imaging αvβ3 expression. Introduction of alternative chelator systems may overcome the

  3. PreS2-TML peptide or guanidinium modified Gd-DOTA exhibits efficient cellular uptake

    Wolf, Markus; Bauder-Wüst, Ulrike; Pipkorn, Rüdiger

    2006-01-01

    The majority of magnetic resonance contrast agents are restricted to the extracellular domains. For the development of novel, intracellular magnetic resonance contrast agents, we have designed Gd-DOTA derivatives comprising PreS2-TML peptide or ethylguanidinium as carrier moiety. Initial in vitro cell uptake studies with Jurkat cells revealed efficient contrast agent uptake for imaging purposes, in the range of 0.04 fmol/cell (PreS2-TML peptide) to 0.2 fmol/cell (ethylguanidinium) followin...

  4. Injectable hydrogels derived from phosphorylated alginic acid calcium complexes

    Kim, Han-Sem; Song, Minsoo, E-mail: minsoosong00@gmail.com; Lee, Eun-Jung; Shin, Ueon Sang, E-mail: usshin12@dankook.ac.kr

    2015-06-01

    Phosphorylation of sodium alginate salt (NaAlg) was carried out using H{sub 3}PO{sub 4}/P{sub 2}O{sub 5}/Et{sub 3}PO{sub 4} followed by acid–base reaction with Ca(OAc){sub 2} to give phosphorylated alginic acid calcium complexes (CaPAlg), as a water dispersible alginic acid derivative. The modified alginate derivatives including phosphorylated alginic acid (PAlg) and CaPAlg were characterized by nuclear magnetic resonance spectroscopy for {sup 1}H, and {sup 31}P nuclei, high resolution inductively coupled plasma optical emission spectroscopy, Fourier transform infrared spectroscopy, and thermogravimetric analysis. CaPAlg hydrogels were prepared simply by mixing CaPAlg solution (2 w/v%) with NaAlg solution (2 w/v%) in various ratios (2:8, 4:6, 6:4, 8:2) of volume. No additional calcium salts such as CaSO{sub 4} or CaCl{sub 2} were added externally. The gelation was completed within about 3–40 min indicating a high potential of hydrogel delivery by injection in vivo. Their mechanical properties were tested to be ≤ 6.7 kPa for compressive strength at break and about 8.4 kPa/mm for elastic modulus. SEM analysis of the CaPAlg hydrogels showed highly porous morphology with interconnected pores of width in the range of 100–800 μm. Cell culture results showed that the injectable hydrogels exhibited comparable properties to the pure alginate hydrogel in terms of cytotoxicity and 3D encapsulation of cells for a short time period. The developed injectable hydrogels showed suitable physicochemical and mechanical properties for injection in vivo, and could therefore be beneficial for the field of soft tissue engineering. - Highlights: • Preparation of water-soluble alginic acid complexes with calcium phosphate • Self-assembly of the phosphorylated alginic acid calcium complexes with sodium alginate • Preparation of injectable hydrogels with diverse gelation times within about 3–40 min.

  5. Stereoselective synthesis of uridine-derived nucleosyl amino acids.

    Spork, Anatol P; Wiegmann, Daniel; Granitzka, Markus; Stalke, Dietmar; Ducho, Christian

    2011-12-16

    Novel hybrid structures of 5'-deoxyuridine and glycine were conceived and synthesized. Such nucleosyl amino acids (NAAs) represent simplified analogues of the core structure of muraymycin nucleoside antibiotics, making them useful synthetic building blocks for structure-activity relationship (SAR) studies. The key step of the developed synthetic route was the efficient and highly diastereoselective asymmetric hydrogenation of didehydro amino acid precursors toward protected NAAs. It was anticipated that the synthesis of unprotected muraymycin derivatives via this route would require a suitable intermediate protecting group at the N-3 of the uracil base. After initial attempts using PMB- and BOM-N-3 protection, both of which resulted in problematic deprotection steps, an N-3 protecting group-free route was envisaged. In spite of the pronounced acidity of the uracil-3-NH, this route worked equally efficient and with identical stereoselectivities as the initial strategies involving N-3 protection. The obtained NAA building blocks were employed for the synthesis of truncated 5'-deoxymuraymycin analogues. PMID:22059552

  6. Effect of DOTA Position on Melanoma Targeting and Pharmacokinetic Properties of 111In-labeled Lactam Bridge-Cyclized Alpha-Melanocyte Stimulating Hormone Peptide

    Guo, Haixun; Yang,Jianquan; Gallazzi, Fabio; Prossnitz, Eric R.; Sklar, Larry A.; Miao, Yubin

    2009-01-01

    The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (α-MSH) peptide.

  7. Anti-Inflammatory Activity of Tanzawaic Acid Derivatives from a Marine-Derived Fungus Penicillium steckii 108YD142

    Hee Jae Shin; Gam Bang Pil; Soo-Jin Heo; Hyi-Seung Lee; Jong Seok Lee; Yeon-Ju Lee; Jihoon Lee; Ho Shik Won

    2016-01-01

    Chemical investigation of a marine-derived fungus, Penicillium steckii 108YD142, resulted in the discovery of a new tanzawaic acid derivative, tanzawaic acid Q (1), together with four known analogues, tanzawaic acids A (2), C (3), D (4), and K (5). The structures of tanzawaic acid derivatives 1–5 were determined by the detailed analysis of 1D, 2D NMR and LC-MS data, along with chemical methods and literature data analysis. These compounds significantly inhibited nitric oxide (NO) production a...

  8. Evaluation of a new biotin-DOTA conjugate for pretargeted antibody-guided radioimmunotherapy (PAGRIT registered)

    A novel biotin-DOTA conjugate (r-BHD: reduced biotinamidohexylamine-DOTA) was investigated in order to provide an efficient pretargeted antibody-guided radioimmunotherapy (PAGRIT registered) application. Preclinical and clinical results are described. 90Y and 177Lu were used to label r-BHD. The effect of pH and a wide range of specific activities were studied. Radiolabelled r-BHD was tested for affinity towards avidin and for stability in saline or in human serum with and without ascorbic acid. Pharmacokinetic data were collected and organ biodistribution evaluated in a tumour-bearing pretargeted animal model. A pilot study was performed in a metastatic melanoma patient and dosimetry was estimated. High radiochemical purity (>99%) was routinely achieved with 90Y or 177Lu in sodium acetate buffer (1.0 M, pH 5.0) at a specific activity of 2.6 MBq/nmol. Both 90Y- and 177Lu-r-BHD were also prepared at higher specific activities. Radiolabelled r-BHD was stable up to 96 h in human serum and saline with the addition of ascorbic acid. The structural modifications proposed for the r-BHD stabilised it against enzymatic degradation while retaining high binding affinity for avidin. Renal clearance appeared to be the main route of excretion in animals, and high tumour uptake was observed in the pretargeted animals. The patient study showed a total body clearance of ∝85% in 24 h, with a kidney absorbed dose of 1.5 mGy/MBq. Tumour uptake was rapid and the calculated dose to a 10-mm tumour lesion was ∝12 mGy/MBq. These results indicate that the new biotin-DOTA conjugate may be a suitable candidate for pretargeting trials. (orig.)

  9. Magnetofluorescent micelles incorporating Dy(III)-DOTA as potential bimodal agents for optical and high field magnetic resonance imaging.

    Harris, Michael; Vander Elst, Luce; Laurent, Sophie; Parac-Vogt, Tatjana N

    2016-03-21

    Dysprosium(iii) was coordinated to four 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) bisamide derivatives functionalized with amphiphilic p-dodecylaniline and p-tetradecylaniline in a differing cis- and trans-orientation. The complexes were assembled into mono-disperse micelles having size distribution maxima ranging from 10 to 15 nm and the magnetic and optical properties of the micelles were examined in detail. The micelles show characteristic Dy(iii) emission with quantum yields reaching 0.8%. The transverse relaxivity r2 per Dy(iii) ion at 500 MHz and 310 K reaches maximum values of ca. 20 s(-1) mM(-1) which is a large increase when compared to a value of 0.8 s(-1) mM(-1) observed for Dy(III)-DTPA. The micelles were stable in water when incubated at 37 °C for 1 week and showed no relaxivity decrease when measured in the presence of 4% (w/v) human serum albumin. The efficient T2 relaxation, especially at strong magnetic fields, is sustained by the high magnetic moment of the dysprosium(iii) ion, the coordination of water molecules and long rotational correlation times. PMID:26865457

  10. Synthesis and biological evaluation of 90Y-labeled porphyrin-DOTA conjugate for targeted tumor therapy

    Development of tumor-avid substances has received considerable attention in current cancer diagnostic and therapeutic protocols. Among the various substances exhibiting tumor specificity, hematoporphyrin and its derivatives have been extensively investigated with the aim to identifying potential agents for targeted tumor diagnosis and therapy. Working in this direction, a water soluble unsymmetrical porphyrin, namely 5-(4-(3-amino)-n-propyloxyphenyl)-10,15,20-tris-(4 carboxymethyleneoxyphenyl)porphyrin was synthesized and subsequently coupled with a bi-functional chelating agent (BFCA), namely p-isothiocyanato-benzyl-1,4,7,10 -tetraazacyclododecane- 1,4,7,10-tetraacetic acid (p-NCS-benzyl-DOTA), for its radiolabeling with 90Y. 90Y was chosen as a therapeutic radionuclide owing to its suitable nuclear decay characteristics (Eβmax= 2.28 MeV, T1/2= 64h) and easy availability in high radionuclidic purity from a 90Sr-90Y generator. The emission of high energy β- particle makes it a suitable candidate for therapy in large-sized tumors

  11. Comparison of 111In-DOTA-DPhe1-Tyr3-octreotide and 111In-DOTA-lanreotide scintigraphy and dosimetry in patients with neuroendocrine tumours

    Somatostatin receptor scintigraphy with 111In-DOTA-DPhe1-Tyr3-octreotide (111In-DOTA-TOC) and 111In-DOTA-lanreotide (111In-DOTA-LAN) has been used for staging of neuroendocrine tumours (NETs). However, the comparative diagnostic value of these radioligands on a lesion basis has not yet been established. The aim of this study was to compare the diagnostic capacity of 111In-DOTA-TOC and 111In-DOTA-LAN scintigraphy in patients with NETs, evaluating whether significant differences exist in lesion imaging with these radioligands. Furthermore, dosimetric data were compared. Forty-five patients with NETs were investigated with 111In-DOTA-TOC and 111In-DOTA-LAN scintigraphy. Scintigraphic results were compared with those of conventional imaging and/or surgery in each patient, and also 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in 20 patients. 111In-DOTA-TOC and 111In-DOTA-LAN scintigraphy were true positive in 42/45 (93%) and 39/45 (87%) patients, and imaged 74/91 (81%) and 73/91 (80%) tumour lesions, respectively. 111In-DOTA-TOC and 111In-DOTA-LAN detected liver metastases in 21 and 14 patients, mediastinal metastases in seven and 11 patients, and bone metastases in two and seven patients, respectively. These radioligands revealed lesions not seen by conventional imaging in seven and eight patients, respectively, or by 18F-FDG-PET in eight and seven patients, respectively. The estimated tumour absorbed doses for 90Y-DOTA-TOC were higher than those for 90Y-DOTA-LAN in 14 patients, whereas the opposite was true in 12 patients. Both 111In-DOTA-TOC and 111In-DOTA-LAN are suitable for imaging tumour lesions in patients with NETs and can detect lesions that may not be seen by conventional imaging and 18F-FDG-PET. Compared with 111In-DOTA-LAN, 111In-DOTA-TOC has a superior diagnostic capacity for liver metastases, but a lower diagnostic capacity for metastatic lesions in mediastinum and bone. (orig.)

  12. A potential plant-derived antifungal acetylenic acid mediates its activity by interfering with fatty acid homeostasis

    6-Nonadecynoic acid (6-NDA), a plant-derived acetylenic acid, exhibits strong inhibitory activity against the human fungal pathogens Candida albicans, Aspergillus fumigatus, and Trichophyton mentagrophytes. In the present study, transcriptional profiling coupled with mutant and biochemical analyses...

  13. Preparation and Biodistribution Evaluation in Mice of ~(177)Lu-DOTA-TOC

    2011-01-01

    The study of 177Lu labeled radiopharmaceuticals for cancer therapy is fast emerging as an important part of nuclear medicine. 177Lu-labelling of DOTA derivatized peptide DOTA-TOC (Tyr3-Octreotide) was carried out and biodistribution of 177Lu-DOTA-TOC in normal

  14. Preparation and biological studies of 68Ga-DOTA-alendronate

    Ashraf Fakhari

    2016-07-01

    Full Text Available Objective(s: In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA conjugated alendronate (DOTA-ALN was synthesized and evaluated after labeling with gallium-68 (68Ga.Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5 at 92-95°C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation,biodistribution studies, and imaging were performed on the developed agent in normal rats.Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320GBq/mmol after solid phase purification and was stabilized for up to 90 min with a logP value of -2.91. Maximum ligand binding (65% was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (

  15. Preparation and Biological Study of 68Ga-DOTA-alendronate

    Fakhari, Ashraf; Jalilian, Amir R.; Johari-Daha, Fariba; Shafiee-Ardestani, Mehdi; Khalaj, Ali

    2016-01-01

    Objective(s): In line with previous research on the development of conjugated bisphosphonate ligands as new bone-avid agents, in this study, DOTA-conjugated alendronate (DOTA-ALN) was synthesized and evaluated after labeling with gallium-68 (68Ga). Methods: DOTA-ALN was synthesized and characterized, followed by 68Ga-DOTA-ALN preparation, using DOTA-ALN and 68GaCl3 (pH: 4-5) at 92-95° C for 10 min. Stability tests, hydroxyapatite assay, partition coefficient calculation, biodistribution studies, and imaging were performed on the developed agent in normal rats. Results: The complex was prepared with high radiochemical purity (>99% as depicted by radio thin-layer chromatography; specific activity: 310-320 GBq/mmol) after solid phase purification and was stabilized for up to 90 min with a log P value of -2.91. Maximum ligand binding (65%) was observed in the presence of 50 mg of hydroxyapatite; a major portion of the activity was excreted through the kidneys. With the exception of excretory organs, gastrointestinal tract organs, including the liver, intestine, and colon, showed significant uptake; however, the bone uptake was low (<1%) at 30 min after the injection. The data were also confirmed by sequential imaging at 30-90 min following the intravenous injection. Conclusion: The high solubility and anionic properties of the complex led to major renal excretion and low hydroxyapatite uptake; therefore, the complex failed to demonstrate bone imaging behaviors. PMID:27408898

  16. Somatostatin-based radiopeptide therapy with [{sup 177}Lu-DOTA]-TOC versus [{sup 90}Y-DOTA]-TOC in neuroendocrine tumours

    Romer, A.; Seiler, D.; Brunner, P.; Ng, Q.K.T.; Mueller-Brand, J. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); Marincek, N.; Walter, M.A. [University Hospital Basel, Institute of Nuclear Medicine, Basel (Switzerland); University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); Koller, M.T. [University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); Maecke, H.R. [University Hospital Basel, Division of Radiochemistry, Basel (Switzerland); Rochlitz, C. [University Hospital Basel, Department of Oncology, Basel (Switzerland); Briel, M. [University Hospital Bern, Institute of Nuclear Medicine, Bern (Switzerland); University Hospital Basel, Basel Institute for Clinical Epidemiology and Biostatistics, Basel (Switzerland); McMaster University, Department of Clinical Epidemiology and Biostatistics, Hamilton (Canada); Schindler, C. [University of Basel, Swiss Tropical and Public Health Institute, Basel (Switzerland)

    2014-02-15

    Somatostatin-based radiopeptide treatment is generally performed using the β-emitting radionuclides {sup 90}Y or {sup 177}Lu. The present study aimed at comparing benefits and harms of both therapeutic approaches. In a comparative cohort study, patients with advanced neuroendocrine tumours underwent repeated cycles of [{sup 90}Y-DOTA]-TOC or [{sup 177}Lu-DOTA]-TOC until progression of disease or permanent adverse events. Multivariable Cox regression and competing risks regression were employed to examine predictors of survival and adverse events for both treatment groups. Overall, 910 patients underwent 1,804 cycles of [{sup 90}Y-DOTA]-TOC and 141 patients underwent 259 cycles of [{sup 177}Lu-DOTA]-TOC. The median survival after [{sup 177}Lu-DOTA]-TOC and after [{sup 90}Y-DOTA]-TOC was comparable (45.5 months versus 35.9 months, hazard ratio 0.91, 95 % confidence interval 0.63-1.30, p = 0.49). Subgroup analyses revealed a significantly longer survival for [{sup 177}Lu-DOTA]-TOC over [{sup 90}Y-DOTA]-TOC in patients with low tumour uptake, solitary lesions and extra-hepatic lesions. The rate of severe transient haematotoxicities was lower after [{sup 177}Lu-DOTA]-TOC treatment (1.4 vs 10.1 %, p = 0.001), while the rate of severe permanent renal toxicities was similar in both treatment groups (9.2 vs 7.8 %, p = 0.32). The present results revealed no difference in median overall survival after [{sup 177}Lu-DOTA]-TOC and [{sup 90}Y-DOTA]-TOC. Furthermore, [{sup 177}Lu-DOTA]-TOC was less haematotoxic than [{sup 90}Y-DOTA]-TOC. (orig.)

  17. Study of Thiosemicarbazone Derivative of Essential Fatty Acid

    Borhade, Shobha

    2014-01-01

    Essential fatty acids results in numerous health benefits. Only two fatty acids are known to be essential for human alpha-linolenic acid (an omega-3 fatty acid) and linoleic acid (an omega-6 fatty acid).The importance of omega-3 fatty acids for physical well-being has been recognised for several decades . Omega-3 fatty acids have anti-inflammatory, antithrombotic, antiarrhythmic and hypolipidaemic effects. Cannabis sativa (Hemp) is an angiosperm belonging to the cannabaceae family and cannabi...

  18. 68Ga-Autoclabeling of DOTA-TATE and DOTA-NOC

    Introduction: A new method combining 68Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC. Methods: The two peptides DOTA-TATE and -NOC were labeled with 68Ga by heating for 15 min at 121 °C in the presence of acetate buffer at pH 4.3. The product solutions were tested for sterility, presence of endotoxins, degradation of peptide and osmolality. Results: Complete incorporation of 68Ga was obtained after the autoclabeling reaction and no degradation of the peptides was observed. Sterility was verified and the presence of endotoxins was well within Ph. Eur limits (175IU/maximum injected volume). Conclusions: The autoclabeling method provides a convenient procedure for 68Ga-labeling by combining the labeling reaction and steam sterilization into one single step. - HighLights: ► We present a one-pot, one-step reaction and sterilization procedure. ► The final product is isotonic and suitable for intravenous injection. ► Total production time, handling and personell dose is minimized. ► Validated and in accordance with Ph. Eur.

  19. {sup 68}Ga-Autoclabeling of DOTA-TATE and DOTA-NOC

    Blom, Elisabeth [Department of Clinical Physiology, 54 P1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev (Denmark); Koziorowski, Jacek, E-mail: jacek@heh.regionh.dk [Department of Clinical Physiology, 54 P1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev (Denmark)

    2012-06-15

    Introduction: A new method combining {sup 68}Ga-labeling and steam sterilization, here called autoclabeling, has been evaluated for two somatostatin receptor binding tracers used for positron emission tomography (PET) imaging of neuroendocrine tumors; DOTA-TATE and -NOC. Methods: The two peptides DOTA-TATE and -NOC were labeled with {sup 68}Ga by heating for 15 min at 121 Degree-Sign C in the presence of acetate buffer at pH 4.3. The product solutions were tested for sterility, presence of endotoxins, degradation of peptide and osmolality. Results: Complete incorporation of {sup 68}Ga was obtained after the autoclabeling reaction and no degradation of the peptides was observed. Sterility was verified and the presence of endotoxins was well within Ph. Eur limits (175IU/maximum injected volume). Conclusions: The autoclabeling method provides a convenient procedure for {sup 68}Ga-labeling by combining the labeling reaction and steam sterilization into one single step. - HighLights: Black-Right-Pointing-Pointer We present a one-pot, one-step reaction and sterilization procedure. Black-Right-Pointing-Pointer The final product is isotonic and suitable for intravenous injection. Black-Right-Pointing-Pointer Total production time, handling and personell dose is minimized. Black-Right-Pointing-Pointer Validated and in accordance with Ph. Eur.

  20. Anti-inflammatory effects of hydroxycinnamic acid derivatives

    NF-κB family of transcription factors are involved in numerous cellular processes, including differentiation, proliferation, and inflammation. It was reported that hydroxycinnamic acid derivatives (HADs) are inhibitors of NF-κB activation. Rice bran oil contains a lot of phytosteryl ferulates, one of HADs. We have investigated effects of phytosteryl ferulates on NF-κB activation in macrophage. Cycloartenyl ferulate (CAF), one of phytosteryl ferulates, significantly reduced lipopolysaccharide (LPS)-induced NO production and mRNA expression of inducible NO synthase and cyclooxygenese-2 but upregulated SOD activity. Electrophoresis mobility shift assay revealed that CAF inhibited DNA-binding of NF-κB. CAF and phytosteryl ferulates probably have potentially anti-inflammatory properties

  1. TWO BIOACTIVE FERULIC ACID DERIVATIVES FROM EREMOSTACHYS GLABRA

    Abbas Delazar

    2004-07-01

    Full Text Available Two ferulic acid derivatives, hexacosyl-(E-ferulate [1] and leucosceptoside A [2], have been isolated from the rhizomes of Eremostachys glabra. The chemical structures of these compounds have been elucidated by UV, ESIMS, 1H NMR and 13C NMR spectroscopic analyses, and also by comparing experimental data with respective literature data. The free radical scavenging activity and general toxicity of these compounds have been assessed. While none of these compounds has shown any significant general toxicity in the brine shrimp lethality assay (LD50>1 mg/mL, compounds 1 and 2 displayed significant antioxidant activity in the DPPH assay (RC50 = 0.0976 mg/mL and 0.0148 mg/mL, respectively.

  2. Antioxidant and cytotoxic activity of mono- and bissalicylic acid derivatives

    Đurendić Evgenija A.

    2014-01-01

    Full Text Available A simple synthesis of mono- and bis-salicylic acid derivatives 1-10 by the transesterification of methyl salicylate (methyl 2-hydroxybenzoate with 3-oxapentane-1,5-diol, 3,6- dioxaoctane-1,8-diol, 3,6,9-trioxaundecane-1,11-diol, propane-1,2-diol or 1-aminopropan- 2-ol in alkaline conditions is reported. All compounds were tested in vitro on three malignant cell lines (MCF-7, MDA-MB-231, PC-3 and one non-tumor cell line (MRC- 5. Strong cytotoxicity against prostate PC-3 cancer cells expressed compounds 3, 4, 6, 9 and 10, all with the IC50 less than 10 μmol/L, which were 11-27 times higher than the cytotoxicity of antitumor drug doxorubicin. All tested compounds were not toxic against the non-tumor MRC-5 cell line. Antioxidant activity of the synthesized derivatives was also evaluated. Compounds 2, 5 and 8 were better OH radical scavengers than commercial antioxidants BHT and BHA. The synthesized compounds showed satisfactory scavenger activity, which was studied by QSAR modeling. A good correlation between the experimental variables IC50 DPPH and IC50 OH and MTI (molecular topological indices molecular descriptors and CAA (accessible Connolly solvent surface area for the new compounds 1, 3, and 5 was observed.

  3. Development of high-specific-activity 68Ga-labeled DOTA-rhenium-cyclized α-MSH peptide analog to target MC1 receptors overexpressed by melanoma tumors

    Introduction: A previous report on 68Ga-1,4,7,10-tetraazacyclodedecane-N,N',N'',N'''-tetraacetic acid (DOTA)-Re(Arg11)CCMSH was shown to indicate the imaging agent's potency for early detection of metastatic melanoma. However, the main limiting factor to developing high-specific-activity 68Ga-DOTA-Re(Arg11)CCMSH is the short half-life of 68Ga, which precludes further purification of the agent. To circumvent this problem, we incorporated the microwave technique to rapidly radiolabel the peptide with 68Ga, thereby allowing enough time to include high-performance liquid chromatography (HPLC) purification in the overall procedure. Methods: DOTA-Re(Arg11)CCMSH was radiolabeled with 68Ga in 68Ga-DOTA-Re(Arg11)CCMSH was then administered on B16/F1 murine melanoma-bearing C57 mice to study its biodistribution and positron emission tomography (PET) imaging capability. Results: The production of high-specific-activity 68Ga-DOTA-Re(Arg11)CCMSH resulted in an improved tumor uptake [6.93±1.11%ID/g at 30 min postinjection (p.i.) and 6.27±1.60%ID/g at 1 h p.i.] and tumor retention (5.85±1.32%ID/g at 4 h p.i.). Receptor-mediated tumor uptake was verified by blocking studies. Furthermore, high-resolution PET images of the tumor were obtained, owing to high tumor-to-nontarget organ ratios at an early time point (i.e., at 1 h biodistribution: tumor/blood, 14.3; tumor/muscle, 89.6; tumor/skin, 12.3) and fast clearance of the labeled peptide from kidney and other healthy tissues. Conclusion: High-specific-activity 68Ga-DOTA-Re(Arg11)CCMSH may have a potential role in the early diagnosis of metastasized melanoma.

  4. Comparison of [131I]-Tyr3-octreotate and [131I]DOTA-Tyr3-octreotate: the effect of DOTA on the pharmacokinetics and stability

    The introduction of radiolabeled somatostatin analogs for peptide receptor imaging and therapy of neuroendocrine cancer have become a primary focus of interest in nuclear medicine. In this work we studied the possibility of preparing radioiodinated octreotate derivatives, with high stability and favourable kinetic in vivo, because 131I-iodide is most frequently used in therapeutic nuclear medicine and aviable. We studied molar peptide to radionuclide ratio in order to obtain the mono-iodinated peptide (di-iodinated no longer binds to the somatostatin receptor). Like other radioiodinated proteins labeled on constituent tyrosine residues, it was important to study the possibility of dehalogenation in vivo. Despite DOTA chelating group was not necessary to the radioiodination procedure, we intended to evaluate the influence of the chelating group on the pharmacokinetic and the in vivo stability of the labeled peptide. 131I radiolabeling of Tyr3-octreotate and DOTA-Tyr3-octreotate was performed using Chloramine T method. A solution of 10 μg of peptide/40 μL of PBS (0.05M phosphate-buffered saline pH 7.5) was transferred to an Eppendorf cap. After addition of 10 μL (74 MBq) radioiodine and 5 μL of chloramine T solution (1mg/mL PBS), the cap was carefully stirred and the labeling reaction was allowed to proceed for 3 minutes at room temperature; 5 μL of sodium methabisulfite solution (2mg/mL PBS) was introduced as reducing agent. Radiochemical purity was determined by HPLC (Waters) using a RP C18 column (4.2 x 50 mm, 5 μm, Waters) with UV (230 nm) and radioactivity (Packard Canberra) detection, flow rate of 0.5 mL/minute with a linear gradient of 40-80% (v/v) methanol in 50 mM sodium acetate buffer (pH 5.5) for 20 minutes, maintained for another 25 minutes. Free radioiodine was also determined by horizontal zone electrophoresis (Amershan Pharmacia) on Whatman 1 paper, 0.05M barbital buffer, pH 8.6, 300V, 40 minutes. The stability of the compounds were evaluated

  5. Preparation and quality control and biodistribution studies of [90Y]-DOTA-cetuximab for radioimmunotherapy

    Yttrium-90 is a useful radionuclide for radioimmunotherapy (RIT) and the anti-epidermal growth factor receptor (anti-EGFR) antibody cetuximab is clinicsally approved for the treatment of EGFR-expressing metastatic colorectal cancer and advanced head and neck cancer. Thus in this work radiolabeling of monoclonal anti-EGFR with 90Y for radioimmunotherapy (RIT) is targeted. Cetuximab was successively labeled with [90Y] chloride (74 MBq) 2 mCi after conjugation with macrocyclics bifunctional chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N',N'-tetraacetic acid mono-(N-hydroxysuccinimidyl) ester (DOTA-NHS), purified and concentrated by centrifugation using an Amicon Ultra-15 filter (Millipore, MWCo, 30000). 90Y chloride was obtained by 90Sr/90Y generator. Radiolabeling was completed in 2 h by the addition of DOTA-cetuximab conjugate at 42 °C. The stability of radiolabeled was studied in human serum. Biodistribution studies in normal rats were carried out to determine the radioimmunoconjugate distribution up to 96 h. Radiochemical purity of 92 % (using ITLC) was obtained for final radioimmunoconjugate (Specific activity = 0.55 GBq/mg). Stability of radiolabeled protein in presence of human serum was tested at 37 °C for up to 24 h. Biodistribution studies demonstrated the highest ID/g % in the blood (2.62 ± 0.005 at 24 h) and the liver (2.19 ± 0.001). This study demonstrated that 90Y-DOTA-cetuximab is a potential compound for the treatment of EGFR-expressing cancers. (author)

  6. Determination of peptide content of DOTA-peptides by metal titration and UPLC

    Radiolabelled DOTA-peptides are in use for Peptide Receptor Radionuclide Scintigraphy (PRS) and Therapy (PRRT), e.g with 177Lu-DOTA-TATE or 90Y-DOTATOC. Labelling conditions are frequently critical. Therefore, the ingredients of the reaction, e.g. radiometal (90Y and 177Lu) and DOTA-peptide should be pure and the content known. Quality control of DOTA-peptide, can be performed with various methods, most commonly by UV. There are numerous conditions in which this is hampered, e.g. impurities may also have UV-absorption. The aim of the study was to quantify content and purity of DOTA-peptide

  7. Topology of Legionella pneumophila DotA: an inner membrane protein required for replication in macrophages.

    Roy, C R; Isberg, R.R.

    1997-01-01

    The Legionella pneumophila dotA gene is required for intracellular growth of the bacterium in macrophages. In this study, a structure-function analysis of the DotA protein was conducted to elucidate the role of this protein in L. pneumophila pathogenesis. Translational fusions of dotA to the Escherichia coli phoA and lacZ genes indicated that DotA is an integral cytoplasmic membrane protein with eight membrane-spanning domains. DotA contains two large periplasmic domains of approximately 503 ...

  8. Gallic acid and gallic acid derivatives: effects on drug metabolizing enzymes.

    Ow, Yin-Yin; Stupans, Ieva

    2003-06-01

    Gallic acid and its structurally related compounds are found widely distributed in fruits and plants. Gallic acid, and its catechin derivatives are also present as one of the main phenolic components of both black and green tea. Esters of gallic acid have a diverse range of industrial uses, as antioxidants in food, in cosmetics and in the pharmaceutical industry. In addition, gallic acid is employed as a source material for inks, paints and colour developers. Studies utilising these compounds have found them to possess many potential therapeutic properties including anti-cancer and antimicrobial properties. In this review, studies of the effects of gallic acid, its esters, and gallic acid catechin derivatives on Phase I and Phase II enzymes are examined. Many published reports of the effects of the in vitro effects of gallic acid and its derivatives on drug metabolising enzymes concern effects directly on substrate (generally drug or mutagen) metabolism or indirectly through observed effects in Ames tests. In the case of the Ames test an antimutagenic effect may be observed through inhibition of CYP activation of indirectly acting mutagens and/or by scavenging of metabolically generated mutagenic electrophiles. There has been considerable interest in the in vivo effects of the gallate esters because of their incorporation into foodstuffs as antioxidants and in the catechin gallates with their potential role as chemoprotective agents. Principally an induction of Phase II enzymes has been observed however more recent studies using HepG2 cells and primary cultures of human hepatocytes provide evidence for the overall complexity of actions of individual components versus complex mixtures, such as those in food. Further systematic studies of mechanisms of induction and inhibition of drug metabolising enzymes by this group of compounds are warranted in the light of their distribution and consequent ingestion, current uses and suggested therapeutic potential. However, it

  9. Result Prediction by Mining Replays in Dota 2

    Johansson, Filip; Wikström, Jesper

    2015-01-01

    Context: Real-time games like Dota 2 lack the extensive mathematical modeling of turn-based games that can be used to make objective statements about how to best play them. Understanding a real-time computer game through the same kind of modeling as a turn-based game is practically impossible. Objectives: In this thesis an attempt was made to create a model using machine learning that can predict the winning team of a Dota 2 game given partial data collected as the game progressed. A couple o...

  10. Preparation & in vitro evaluation of 90Y-DOTA-rituximab

    Mythili Kameswaran; Usha Pandey; Ashutosh Dash; Grace Samuel; Meera Venkatesh

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with [90] Y and in vitro and in vivo ev...

  11. Preparation & in vitro evaluation of 90 Y-DOTA-rituximab

    Mythili Kameswaran; Usha Pandey; Ashutosh Dash; Grace Samuel; Meera Venkatesh

    2016-01-01

    Background & objectives: Radioimmunotherapy is extensively being used for the treatment of non-Hodgkin′s lymphoma (NHL). Use of rituximab, a chimeric anti-CD20 antibody directed against the CD20 antigen in combination with suitable beta emitters is expected to result in good treatment response by its cross-fire and bystander effects. The present work involves the conjugation of p-isothiocyanatobenzyl DOTA (p-SCN-Bn-DOTA) to rituximab, its radiolabelling with [90] Y and in vitro and in vivo ev...

  12. Synthesis of -acylurea derivatives from carboxylic acids and ,' -dialkyl carbodiimides in water

    Ali Ramazani; Fatemeh Zeinali Nasrabadi; Aram Rezaei; Morteza Rouhani; Hamideh Ahankar; Pegah Azimzadeh Asiabi; Sang Woo Joo; Katarzyna Ślepokura; Tadeusz Lis

    2015-12-01

    Reactions of benzoic acid derivatives and ()-cinnamic acid derivatives with , '-dialkyl carbodiimide proceed smoothly at room temperature and in neutral conditions to afford -acylurea derivatives in high yields. The reaction proceeds smoothly and cleanly under mild conditions and no side reactions were observed.

  13. Investigation of molecular interactions in the complex formation of tartaric acid derivatives with di(2-ethylhexyl) phosphoric acid

    2008-01-01

    The molecular interactions in the complex formation of two tartaric acid derivatives with di(2-ethylhexyl) phosphoric acid are investigated. The complex formation with a 1:1 stoichiometry between tartaric acid derivatives and D2EHPA can be obtained through UV-Vis titration, NMR chemical shifts and molecular dynamic simulations. Furthermore, the differences of the two complexes on the binding constants and strength of hydrogen bonds can also be determined. Such research will ideally provide insight into ways of regulating the complex forming properties of tartaric acid derivatives for composing or syn- thesizing new chiral resolving agents.

  14. Investigation of molecular interactions in the complex formation of tartaric acid derivatives with di(2-ethylhexyl) phosphoric acid

    TAN Bin; ZHAI Zheng; LUO GuangSheng; WANG JiaDing

    2008-01-01

    The molecular interactions in the complex formation of two tartaric acid derivatives with di(2-ethylhexyl) phosphoric acid are investigated. The complex formation with a 1:1 stoichiometry between tartaric acid derivatives and D2EHPA can be obtained through UV-Vis titration, NMR chemical shifts and molecular dynamic simulations. Furthermore, the differences of the two complexes on the binding constants and strength of hydrogen bonds can also be determined. Such research will ideally provide insight into ways of regulating the complex forming properties of tartaric acid derivatives for composing or syn-thesizing new chiral resolving agents.

  15. Synthesis of some bis- and mono-2-hydroxybenzoic acid derivatives and the determination of their acidity constants

    KATARINA M. PENOV GASI

    2000-10-01

    Full Text Available Several bis- and mono-2-hydroxybenzoic acid derivatives were synthesized by the reaction of methyl 2-hydroxybenzoate with some alcohols (diols, polyols and amino alcohols and their acidity constants were determined in 60 % aqueous ethanol by the potentiometric titration method. It has been shown that the biochemical behaviour of these compounds is greatly dependent on their acidity. It appears that the ester derivatives are weaker acids than the amide derivatives and, therefore, can be potentially more involved in the processes of metal ions transport in plants, whereas the introduction of –OH and –CH3 groups has a very small effect on the biochemical properties.

  16. Cannabimimetic fatty acid derivatives in cancer and inflammation.

    Di Marzo, V; Melck, D; De Petrocellis, L; Bisogno, T

    2000-04-01

    Evidence for the role of the cannabimimetic fatty acid derivatives (CFADs), i.e. anandamide (arachidonoylethanolamide, AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA), in the control of inflammation and of the proliferation of tumor cells is reviewed here. The biosynthesis of AEA, PEA, or 2-AG can be induced by stimulation with either Ca(2+) ionophores, lipopolysaccharide, or platelet activating factor in macrophages, and by ionomycin or antigen challenge in rat basophilic leukemia (RBL-2H3) cells (a widely used model for mast cells). These cells also inactivate CFADs through re-uptake and/or hydrolysis and/or esterification processes. AEA and PEA modulate cytokine and/or arachidonate release from macrophages in vitro, regulate serotonin secretion from RBL-2H3 cells, and are analgesic in some animal models of inflammatory pain. However, the involvement of endogenous CFADs and cannabinoid CB(1) and CB(2) receptors in these effects is still controversial. In human breast and prostate cancer cells, AEA and 2-AG, but not PEA, potently inhibit prolactin and/or nerve growth factor (NGF)-induced cell proliferation. Vanillyl-derivatives of anandamide, such as olvanil and arvanil, exhibit even higher anti-proliferative activity. These effects are due to suppression of the levels of the 100 kDa prolactin receptor or of the high affinity NGF receptors (trk), are mediated by CB(1)-like cannabinoid receptors, and are enhanced by other CFADs. Inhibition of adenylyl cyclase and activation of mitogen-activated protein kinase underlie the anti-mitogenic actions of AEA. The possibility that CFADs act as local inhibitors of the proliferation of human breast cancer is discussed here. PMID:10785541

  17. Comparative biodistributions and dosimetry of [177Lu]DOTA-anti-bcl-2-PNA-Tyr3-octreotate and [177Lu]DOTA-Tyr3-octreotate in a mouse model of B-cell lymphoma/leukemia

    Introduction: The B-cell lymphoma/leukemia-2 (bcl-2) proto-oncogene in non-Hodgkin’s lymphoma (NHL) is a dominant inhibitor of apoptosis. We developed a 177Lu-labeled bcl-2 antisense peptide nucleic acid (PNA)–peptide conjugate designed for dual modality NHL therapy, consisting of a radiopharmaceutical capable of simultaneously down-regulating apoptotic resistance and delivering cytotoxic internally emitted radiation. Methods: DOTA-anti-bcl-2-Tyr3-octreotate was synthesized, labeled with 177Lu, and purified using RP-HPLC. The PNA–peptide conjugate was evaluated in Mec-1 NHL-bearing mice and compared to [177Lu]DOTA-Tyr3-octreotate in biodistribution and excretion studies. These data were then used to generate in vivo dosimetry models. Results: The PNA–peptide conjugate was readily prepared and radiolabeled in high yield and radiochemical purity. An in vivo blocking study determined that administration of 50 μg of non-radioactive PNA–peptide was the optimal mass for maximum delivery to the tumor. Based on that result, a dosing regimen of 177Lu-PNA–peptide, for radiologic effect, followed by the optimal mass of non-radioactive compound, for antisense effect, was designed. Using that dosing regimen, biodistribution of the PNA–peptide showed uptake in the tumor with minimal washout over a 4-day period. Uptakes in receptor-positive normal organs were low and displayed nearly complete washout by 24 h. Dosimetry models showed that the tumor absorbed dose of the PNA–peptide conjugate was approximately twice that of the peptide-only conjugate. Conclusions: Biodistribution data showed specific tumor targeting of the 177Lu-labeled PNA–peptide compound with minimal receptor-positive normal tissue uptake when compared to [177Lu]DOTA-Tyr3-octreotate. In vivo dosimetry models predicted a more favorable tumor absorbed dose from [177Lu]DOTA-anti-bcl-2-Tyr3-octreotate

  18. Discotic liquid crystal derived from zinc tetraaminophthalocyanine and perfluorooctanoic acid

    Meng, Fanbao; Zhou, Naiyu; Diao, Na; Du, Chang

    2013-12-01

    A novel kind of metallo-phthalocyanine derivative, zinc 2,9,16,23-tetraaminophthalocyanine perfluorooctanoate (Zn-APc-pFOA), was synthesized from zinc tetraaminophthalocyanine and perfluorooctanoic acid. The chemical structure, liquid crystalline behavior, and electrorheological properties were characterized by the use of various experimental techniques, methods, and instruments, including FT-IR and UV-vis spectroscopy, 1H-NMR, x-ray diffraction, differential scanning calorimetry, thermogravimetric analysis, polarized optical microscopy, the four-point method, a relative permittivity test instrument, and a rotating viscometer. Zn-APc-pFOA shows a discotic hexagonal columnar mesophase over a wide temperature range. The dielectric constant and conductivity of Zn-APc-pFOA are 11.4 and 6.34 × 10-3 S cm-1, respectively. The 20 V% silicone oil-Zn-APc-pFOA fluid shows an electrorheological (ER) effect. Zn-APc-pFOA is a semiconductor with a high dielectric constant, causing a mismatch of conductivity and dielectric constant between the Zn-APc-pFOA and silicone oil. Furthermore, some synergistic effect could occur between the semiconducting property and the molecular orientation of the discotic liquid crystals in Zn-APc-pFOA suspensions, resulting in a high ER effect.

  19. Benzoic acid derivatives from Piper species and their antiparasitic activity.

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2008-09-01

    Piper glabratum and P. acutifolium were analyzed for their content of main secondary constituents, affording nine new benzoic acid derivatives (1, 2, 4, 5, 7, and 10-13), in addition to four known compounds (3, 6, 8, and 9). Their structures were elucidated on the basis of spectroscopic data. Riguera ester reactions and optical rotation measurements established the new compounds as racemates. In the search for antiparasitic agents, the compounds were evaluated in vitro against the promastigote forms of Leishmania spp., Trypanosoma cruzi, and Plasmodium falciparum. Among the evaluated compounds, methyl 3,4-dihydroxy-5-(3'-methyl-2'-butenyl)benzoate (7) exhibited leishmanicidal effect (IC50 13.8-18.5 microg/mL) against the three Leishmania strains used, and methyl 3,4-dihydroxy-5-(2-hydroxy-3-methylbutenyl)benzoate (1), methyl 4-hydroxy-3-(2-hydroxy-3-methyl-3-butenyl)benzoate (3), and methyl 3,4-dihydroxy-5-(3-methyl-2-butenyl) benzoate (7) showed significant trypanocidal activity, with IC50 values of 16.4, 15.6, and 18.5 microg/mL, respectively. PMID:18712933

  20. Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives

    Vepsäläinen Jouko J; Turhanen Petri A

    2006-01-01

    Abstract A novel strategy for the synthesis of (1-alkanoyloxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (1a-d) via (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), starting from alendronate has been developed with reasonable 51–77% overall yields. Intermediate products, (1-hydroxy-4-alkanoylaminobutylidene)-1,1-bisphosphonic acid derivatives (2a-d), were prepared in water with reasonable to high yields (52–94%).

  1. Synthesis of novel (1-alkanoyloxy-4-alkanoylaminobutylidene-1,1-bisphosphonic acid derivatives

    Vepsäläinen Jouko J

    2006-02-01

    Full Text Available Abstract A novel strategy for the synthesis of (1-alkanoyloxy-4-alkanoylaminobutylidene-1,1-bisphosphonic acid derivatives (1a-d via (1-hydroxy-4-alkanoylaminobutylidene-1,1-bisphosphonic acid derivatives (2a-d, starting from alendronate has been developed with reasonable 51–77% overall yields. Intermediate products, (1-hydroxy-4-alkanoylaminobutylidene-1,1-bisphosphonic acid derivatives (2a-d, were prepared in water with reasonable to high yields (52–94%.

  2. The Synthesis of Some Novel N-[a-(Isoflavone-7-O-)Acetyl ] Amino Acid Derivatives

    2000-01-01

    A series of novel N-[(α)-(isoflavone-7-O-)acetyl] amino acid methyl esters were prepared from the efficient and regioselective alkylation of isoflavones with chloroacetyl amino acid derivatives under mild condition.

  3. Procedure guidelines for PET/CT tumour imaging with 68Ga-DOTA-conjugated peptides: 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, 68Ga-DOTA-TATE.

    Virgolini, I.; Ambrosini, V.; Bomanji, J.B.; Baum, R.P.; Fanti, S.; Gabriel, M.; Papathanasiou, N.D.; Pepe, G.; Oyen, W.J.G.; Cristoforo, C. De; Chiti, A.

    2010-01-01

    The aim of these guidelines is to assist nuclear medicine physicians in recommending, performing, reporting and interpreting the results of somatostatin (SST) receptor PET/CT imaging using 68Ga-DOTA-conjugated peptides, analogues of octreotide, that bind to SST receptors. This imaging modality shoul

  4. Tumor targeting using {sup 67}Ga-DOTA-Bz-folate - investigations of methods to improve the tissue distribution of radiofolates

    Mueller, Cristina, E-mail: cristina.mueller@psi.ch [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Vlahov, Iontcho R.; Santhapuram, Hari Krishna R.; Leamon, Christopher P. [Endocyte Inc., West Lafayette, IN 47906 (United States); Schibli, Roger [Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institute, 5232 Villigen-PSI (Switzerland); Department of Chemistry and Applied Biosciences, ETH Zurich, 8093 Zurich (Switzerland)

    2011-07-15

    Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [{sup 67}Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-({gamma})-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with {sup 67}GaCl{sub 3} according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: {sup 67}Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%{+-}0.75% ID/g, 1 h pi and 6.08%{+-}0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of {sup 67}Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel {sup 67}Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR

  5. PET imaging of tumor neovascularization in a transgenic mouse model with a novel 64Cu-DOTA-knottin peptide

    Nielsen, Carsten Haagen; Kimura, Richard H; Withofs, Nadia;

    2010-01-01

    the knottin peptide are compared with standard 18F-fluorodeoxyglucose (FDG) PET small animal imaging. Lung nodules as small as 3 mm in diameter were successfully identified in the transgenic mice by small animal CT, and both 64Cu-DOTA-knottin 2.5F and FDG were able to differentiate lung nodules from...... the surrounding tissues. Uptake and retention of the 64Cu-DOTA-knottin 2.5F tracer in the lung tumors combined with a low background in the thorax resulted in a statistically higher tumor to background (normal lung) ratio compared with FDG (6.01±0.61 versus 4.36±0.68; P...... animal CT followed by characterization with the use of small animal PET with a novel 64Cu-1,4,7,10-tetra-azacylododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-knottin peptide that targets integrins upregulated during angiogenesis on the tumor associated neovasculature. The imaging results obtained with...

  6. Imidazol and barbituric acid derivatives - heterocyclic carbene fragments with pi-donor and acceptor properties

    Sweidan, Kamal

    2006-01-01

    New derivatives of 1,3-dimethylbarbituric acid and imidazol-2-ylidene were prepared and characterized by different spectroscopic techniques. The resulting derivatives are classified into zwitterionic, salts and neutral derivatives of 1,3-dimethylbarbituric acid and salts derivatives of 2,3-dihydroimidazole-2-ylidenes. The crystal structures of most of these compounds reveal the presence of N-H-O and C-H-O hydrogen bonds.

  7. Pharmaceuticals and Surfactants from Alga-Derived Feedstock: Amidation of Fatty Acids and Their Derivatives with Amino Alcohols.

    Tkacheva, Anastasia; Dosmagambetova, Inkar; Chapellier, Yann; Mäki-Arvela, Päivi; Hachemi, Imane; Savela, Risto; Leino, Reko; Viegas, Carolina; Kumar, Narendra; Eränen, Kari; Hemming, Jarl; Smeds, Annika; Murzin, Dmitry Yu

    2015-08-24

    Amidation of renewable feedstocks, such as fatty acids, esters, and Chlorella alga based biodiesel, was demonstrated with zeolites and mesoporous materials as catalysts and ethanolamine, alaninol, and leucinol. The last two can be derived from amino acids present in alga. The main products were fatty alkanol amides and the corresponding ester amines, as confirmed by NMR and IR spectroscopy. Thermal amidation of technical-grade oleic acid and stearic acid at 180 °C with ethanolamine were non-negligible; both gave 61% conversion. In the amidation of stearic acid with ethanolamine, the conversion over H-Beta-150 was 80% after 3 h, whereas only 63% conversion was achieved for oleic acid; this shows that a microporous catalyst is not suitable for this acid and exhibits a wrinkled conformation. The highest selectivity to stearoyl ethanolamide of 92% was achieved with mildly acidic H-MCM-41 at 70% conversion in 3 h at 180 °C. Highly acidic catalysts favored the formation of the ester amine, whereas the amide was obtained with a catalyst that exhibited an optimum acidity. The conversion levels achieved with different fatty acids in the range C12-C18 were similar; this shows that the fatty acid length does not affect the amidation rate. The amidation of methyl palmitate and biodiesel gave low conversions over an acidic catalyst, which suggested that the reaction mechanism in the amidation of esters was different. PMID:26197759

  8. Metabolic engineering of yeast to produce fatty acid-derived biofuels: bottlenecks and solutions.

    Sheng, Jiayuan; Feng, Xueyang

    2015-01-01

    Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles. PMID:26106371

  9. Tumour uptake of the radiolabelled somatostatin analogue [DOTA0,TYR3]octreotide is dependent on the peptide amount

    Radiolabelled tumour receptor-binding peptides can be used for in vivo scintigraphic imaging. Recently, the somatostatin analogue [Tyr3]octreotide (d-Phe-c(Cys-Tyr-d-Trp-Lys-Thr-Cys)-Thr(ol)) was derivatized with the chelator DOTA (tetra-azacyclododecane-tetra-acetic acid), enabling stable radiolabelling with both the high-energy beta particle-emitter yttrium-90 and the Auger electron-emitter indium-111. The thus produced radiolabelled compounds are promising for peptide receptor radionuclide therapy. Our previous in vitro and in vivo (rat) experiments with these radiolabelled compounds showed favourable binding and biodistribution characteristics with high uptake and retention in the target organs. We also demonstrated receptor-specific, time- and temperature-dependent internalization of radiolabelled [DOTA0,Tyr3]octreotide in somatostatin receptor subtype 2 (sst2)-positive rat pancreatic tumour cell lines. In this study we have investigated the effects of differences in the amount of injected peptide on tissue distribution of 111In-labelled [DOTA0,Tyr3]octreotide in normal, i.e. non-tumour-bearing, and CA20948 tumour-bearing rats. This was done in order to find the amount of peptide at which the highest uptake in target tissues is achieved, and thereby to increase the potential of radionuclide therapy while simultaneously ensuring the lowest possible radiotoxicity in normal organs. Uptake of radiolabelled [DOTA0,Tyr3]octreotide in sst2-positive organs showed different bell-shaped functions of the amount of injected peptide, being highest at 0.05 (adrenals), 0.05-0.1 (pituitary and stomach) and 0.25 (pancreas) μg. Uptake in the tumour was highest at 0.5 μg injected peptide. The highest uptake was found at peptide amounts that were lower than those reported for [111In-DTPA0]octreotide (d-Phe-c(Cys-Phe-d-Trp-Lys-Thr-Cys)-Thr(ol), DTPA = diethylene-triamine-penta-acetic acid), consistent with the higher receptor affinity of the first compound. Our observations of

  10. Some New Derivatives of Organozirconium(IV) with Pyridinedicarboxylic Acids

    Satish C. Dixit; Rohit K. Singh

    2012-01-01

    Reactions of dichlorobis(cyclopentadienyl)zirconium(IV) with pyridinedicarboxylic acids viz. quinolinic acids (QAH2), 2,4-pyridine dicarboxylic acid (PAH2), isocinchomeronic acid (IAH2), cinchomeronic acid (CAH2) and dinicotinic acid (DAH2) were carried out in different stoichiometric ratios. Complexes of the type Cp2Zr(QAH)Cl, Cp2Zr(QAH)2, Cp2Zr(PAH)Cl, Cp2Zr(PAH)2, Cp2Zr(IAH)Cl, Cp2Zr(IAH)2, Cp2Zr(CAH)Cl, Cp2Zr(CAH)2, Cp2Zr(DAH)Cl and Cp2Zr(DAH)2 were obtained. These new complexes were char...

  11. Somatostatin receptor PET in neuroendocrine tumours: {sup 68}Ga-DOTA{sup 0},Tyr{sup 3}-octreotide versus {sup 68}Ga-DOTA{sup 0}-lanreotide

    Putzer, Daniel; Kroiss, Alexander; Waitz, Dietmar; Gabriel, Michael; Uprimny, Christian; Guggenberg, Elisabeth von; Decristoforo, Clemens; Warwitz, Boris; Virgolini, Irene Johanna [Innsbruck Medical University, Department of Nuclear Medicine, Innsbruck (Austria); Traub-Weidinger, Tatjana [Vienna Medical University, Department of Nuclear Medicine, Vienna (Austria); Widmann, Gerlig [Innsbruck Medical University, Department of Radiology, Innsbruck (Austria)

    2013-03-15

    The aim of this study was to evaluate the impact of {sup 68}Ga-labelled DOTA{sup 0}-lanreotide ({sup 68}Ga-DOTA-LAN) on the diagnostic assessment of neuroendocrine tumour (NET) patients with low to moderate uptake on planar somatostatin receptor (SSTR) scintigraphy or {sup 68}Ga-labelled DOTA{sup 0},Tyr{sup 3}-octreotide ({sup 68}Ga-DOTA-TOC) positron emission tomography (PET). Fifty-three patients with histologically confirmed NET and clinical signs of progressive disease, who had not qualified for peptide receptor radionuclide therapy (PRRT) on planar SSTR scintigraphy or {sup 68}Ga-DOTA-TOC PET (n = 38) due to lack of tracer uptake, underwent {sup 68}Ga-DOTA-LAN PET to evaluate a treatment option with {sup 90}Y-labelled lanreotide according to the MAURITIUS trial. The included patients received 150 {+-} 30 MBq of each radiopharmaceutical intravenously. PET scans were acquired 60-90 min after intravenous bolus injection. Image results from both PET scans were compared head to head, focusing on the intensity of tracer uptake in terms of treatment decision. CT was used for morphologic correlation of tumour lesions. To further evaluate the binding affinities of each tracer, quantitative and qualitative values were calculated for target lesions. {sup 68}Ga-DOTA-LAN and {sup 68}Ga-DOTA-TOC both showed equivalent findings in 24/38 patients when fused PET/CT images were interpreted. The sensitivity, specificity and accuracy of {sup 68}Ga-DOTA-LAN in comparison to CT were 0.63, 0.5 and 0.62 (n = 53; p < 0.0001) and for {sup 68}Ga-DOTA-TOC in comparison to CT 0.78, 0.5 and 0.76 (n = 38; p < 0.013), respectively. {sup 68}Ga-DOTA-TOC showed a significantly higher maximum standardized uptake value (SUV{sub max}) regarding the primary tumour in 25 patients (p < 0.003) and regarding the liver in 30 patients (p < 0.009) compared to {sup 68}Ga-DOTA-LAN. Corresponding values of both PET scans for tumour and liver did not show any significant correlation. {sup 68}Ga-DOTA

  12. CATALYTIC HYDROGENATION AND OXIDATION OF BIOMASS-DERIVED LEVULINIC ACID

    Yan Gong; Lu Lin; Zhipei Yan

    2011-01-01

    Levulinic acid (LA), 4-oxo-pentanoic acid, is a new platform chemical with various potential uses. In this paper, catalytic hydrogenation and oxidation of levulinic acid were studied. It was shown from experiments that levulinic acid can be hydrogenated to γ-valerolactone (GVL) over transition metal catalysts and oxidative-decarboxylated to 2-butanone (methyl-ethyl-ketone, MEK) and methyl-vinyl-ketone (MVK) by cupric oxide (CuO), cupric oxide/cerium oxide (CuO/CeO2), cupric oxide/ alumina (Cu...

  13. CATALYTIC HYDROGENATION AND OXIDATION OF BIOMASS-DERIVED LEVULINIC ACID

    Yan Gong

    2011-02-01

    Full Text Available Levulinic acid (LA, 4-oxo-pentanoic acid, is a new platform chemical with various potential uses. In this paper, catalytic hydrogenation and oxidation of levulinic acid were studied. It was shown from experiments that levulinic acid can be hydrogenated to γ-valerolactone (GVL over transition metal catalysts and oxidative-decarboxylated to 2-butanone (methyl-ethyl-ketone, MEK and methyl-vinyl-ketone (MVK by cupric oxide (CuO, cupric oxide/cerium oxide (CuO/CeO2, cupric oxide/ alumina (CuO/ Al2O3, and silver(I/ peroxydisulfate (Ag(I/S2O82-.

  14. Hydroxyoctadecadienoic acids: Oxidised derivatives of linoleic acid and their role in inflammation associated with metabolic syndrome and cancer.

    Vangaveti, Venkat N; Jansen, Holger; Kennedy, Richard Lee; Malabu, Usman H

    2016-08-15

    Linoleic acid (LA) is a major constituent of low-density lipoproteins. An essential fatty acid, LA is a polyunsaturated fatty acid, which is oxidised by endogenous enzymes and reactive oxygen species in the circulation. Increased levels of low-density lipoproteins coupled with oxidative stress and lack of antioxidants drive the oxidative processes. This results in synthesis of a range of oxidised derivatives, which play a vital role in regulation of inflammatory processes. The derivatives of LA include, hydroxyoctadecadienoic acids, oxo-​octadecadienoic acids, epoxy octadecadecenoic acid and epoxy-keto-octadecenoic acids. In this review, we examine the role of LA derivatives and their actions on regulation of inflammation relevant to metabolic processes associated with atherogenesis and cancer. The processes affected by LA derivatives include, alteration of airway smooth muscles and vascular wall, affecting sensitivity to pain, and regulating endogenous steroid hormones associated with metabolic syndrome. LA derivatives alter cell adhesion molecules, this initial step, is pivotal in regulating inflammatory processes involving transcription factor peroxisome proliferator-activated receptor pathways, thus, leading to alteration of metabolic processes. The derivatives are known to elicit pleiotropic effects that are either beneficial or detrimental in nature hence making it difficult to determine the exact role of these derivatives in the progress of an assumed target disorder. The key may lie in understanding the role of these derivatives at various stages of development of a disorder. Novel pharmacological approaches in altering the synthesis or introduction of synthesised LA derivatives could possibly help drive processes that could regulate inflammation in a beneficial manner. Chemical Compounds: Linoleic acid (PubChem CID: 5280450), 9- hydroxyoctadecadienoic acid (PubChem CID: 5312830), 13- hydroxyoctadecadienoic acid (PubChem CID: 6443013), 9-oxo

  15. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp. §

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-01-01

    Abstract Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic a...

  16. Anacardic acid derived salicylates are inhibitors or activators of lipoxygenases

    Wisastra, Rosalina; Ghizzoni, Massimo; Boltjes, Andre; Haisma, Hidde J.; Dekker, Frank J.

    2012-01-01

    Lipoxygenases catalyze the oxidation of unsaturated fatty acids, such as linoleic acid, which play a crucial role in inflammatory responses. Selective inhibitors may provide a new therapeutic approach for inflammatory diseases. In this study, we describe the identification of a novel soybean lipoxyg

  17. Polyphosphorous acid catalyzed cyclization in the synthesis of cryptolepine derivatives

    2007-01-01

    11-Oxo-10,11-dihydroxy-5H-indolo[3,2,b]quinoline7-carboxylic acid was obtained specifically by polyphosphorous acid catalyzed cyclization with optimal reaction conditions. Biological assays showed that it potentially inhibits the proteasomal chymotrypsin-like activity in vitro and suppresses breast cancer cell growth.

  18. Stability and interactions in mixed monolayers of fatty acid derivatives on artificial sea water

    Brzozowska, A.M.; Mugele, F.; Duits, M.H.G.

    2013-01-01

    We studied the formation and stability of fatty acid and derivatives films on aqueous sub-phases by means of Langmuir trough experiments. Films were prepared from pure stearic acid (SA), stearyl amine (SAm) and 12-phenyldodecanoic acid (PDA), and from binary systems of SA with either SAm or PDA. For

  19. Michael addition of thiols, carbon nucleophiles and amines to dehydroamino acid and dehydropeptide derivatives

    Ferreira, Paula M.T.; Maia, Hernâni L. S.; Monteiro, Luís S.; Sacramento, Joana

    2001-01-01

    Michael additions of nitrogen heterocycles, thiols, carbon nucleophiles and amines to dehydroalanine derivatives, including a glycyldehydroalanine peptide, were performed in fair to good yields. Dehydroaminobutyric acid derivatives reacted only with the stronger nucleophiles but in considerably lower yields and often no reaction was observed with the corresponding dehydrophenylalanine derivatives. When a tosyl group was bonded to the nitrogen atom of the dehydroamino acid, in some cases the a...

  20. Production and Quality Control of [67Ga]-DOTA-trastuzumab for Radioimmunoscintigraphy

    Alirezapour, Behrooz; R. Jalilian, Amir; Bolourinovin, Fatemeh; Moradkhani, Sedigheh

    2013-01-01

    Breast cancer radioimmunoscintigraphy targeting HER2/neu expression is a growing field of work in nuclear medicine research. In this study, trastuzumab was successively labeled with [67Ga] GaCl3 after conjugation with DOTA-NHS-ester. The conjugates were purified by molecular filtration, the average number of DOTA conjugated per mAb was calculated and total concentration was determined by spectrophotometric method. DOTA-Trastuzumab was labeled with 67Ga. Radiochemical purity, integrity of prot...

  1. Antiparasitic activity of prenylated benzoic acid derivatives from Piper species.

    Flores, Ninoska; Jiménez, Ignacio A; Giménez, Alberto; Ruiz, Grace; Gutiérrez, David; Bourdy, Genevieve; Bazzocchi, Isabel L

    2009-03-01

    Fractionation of dichloromethane extracts from the leaves of Piper heterophyllum and P. aduncum afforded three prenylated hydroxybenzoic acids, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid, 3-[(2E,6E,10E)-11-carboxy-13-hydroxy-3,7,15-trimethyl-2,6,10,14-hexadecatetraenyl]-4,5-dihydroxybenzoic acid and 3-[(2E,6E,10E)-11-carboxy-14-hydroxy-3,7,15-trimethyl-2,6,10,15-hexadecatetraenyl]-4,5-dihydroxybenzoic acid, along with the known compounds, 4,5-dihydroxy-3-(E,E,E-11-formyl-3,7,15-trimethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid (arieianal), 3,4-dihydroxy-5-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 4-hydroxy-3-(E,E,E-3,7,11,15-tetramethyl-hexadeca-2,6,10,14-tetraenyl)benzoic acid, 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid, 4-hydroxy-3-(3,7-dimethyl-2,6-octadienyl)benzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid. Their structures were elucidated on the basis of spectroscopic data, including homo- and heteronuclear correlation NMR experiments (COSY, HSQC and HMBC) and comparison with data reported in the literature. Riguera ester reactions and optical rotation measurements established the compounds as racemates. The antiparasitic activity of the compounds were tested against three strains of Leishmania spp., Trypanosoma cruzi and Plasmodium falciparum. The results showed that 3-(3,7-dimethyl-2,6-octadienyl)-4-methoxy-benzoic acid exhibited potent and selective activity against L. braziliensis (IC(50) 6.5 microg/ml), higher that pentamidine used as control. Moreover, 3-[(2E,6E,10E)-11-carboxy-3,7,15-trimethyl- 2,6,10,14-hexadecatetraenyl)-4,5-dihydroxybenzoic acid and 4-hydroxy-3-(3-methyl-1-oxo-2-butenyl)-5-(3-methyl-2-butenyl)benzoic acid showed moderate antiplasmodial (IC(50) 3.2 microg/ml) and trypanocidal (16.5 microg/ml) activities, respectively. PMID:19361822

  2. Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours

    For the internal radiotherapy of neuroendocrine tumours, the somatostatin analogue DOTATOC labelled with 90Y is frequently used [90Y-DOTA-Phe1-Tyr3-octreotide (SMT487-OctreoTher)]. Radiation exposure to the kidneys is critical in this therapy as it may result in renal failure. The aim of this study was to compare cumulative organ and tumour doses based upon dosimetric data acquired with the chemically identical 86Y-DOTA-Phe1-Tyr3-octreotide (considered as the gold standard) and the commercially available 111In-pentetreotide. The cumulative organ and tumour doses for the therapeutic administration of 13.32 GBq 90Y-DOTA-Phe1-Tyr3-octreotide (three cycles, each of 4.44 GBq) were estimated based on the MIRD concept (MIRDOSE 3.1 and IMEDOSE). Patients with a cumulative kidney dose exceeding 27 Gy had to be excluded from subsequent therapy with 90Y-DOTA-Phe1-Tyr3-octreotide, in accordance with the directives of the German radiation protection authorities. The range of doses (mGy/MBq 90Y-DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumour masses was 0.6-2.8, 1.5-4.2, 0.3-1.3 and 2.1-29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively, versus 1.3-3.0, 1.8-4.4, 0.2-0.8 and 1.4-19.7 (111In-pentetreotide), with wide inter-subject variability. Despite renal protection with amino acid infusions, estimated cumulative kidney doses in two patients exceeded 27 Gy. Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumour-free liver was underestimated. However, both dosimetric approaches detected the two patients with an exceptionally high radiation burden to the kidneys that carried a potential risk of renal failure following radionuclide therapy. (orig.)

  3. Validation of 64Cu-DOTA-rituximab injection preparation under good manufacturing practices: a PET tracer for imaging of B-cell non-Hodgkin lymphoma.

    Natarajan, Arutselvan; Arksey, Natasha; Iagaru, Andrei; Chin, Frederick T; Gambhir, Sanjiv Sam

    2015-01-01

    Manufacturing of 64Cu-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-rituximab injection under good manufacturing practices (GMP) was validated for imaging of patients with CD20+ B-cell non-Hodgkin lymphoma. Rituximab was purified by size exclusion high performance liquid chromatography (HPLC) and conjugated to DOTA-mono-(N-hydroxysuccinimidyl) ester. 64CuCl2, buffers, reagents, and other raw materials were obtained as high-grade quality. Following a semi-automated synthesis of 64Cu-DOTA-rituximab, a series of quality control tests was performed. The product was further tested in vivo using micro-positron emission tomography/computed tomography (PET/CT) to assess targeting ability towards human CD20 in transgenic mice. Three batches of 64Cu-DOTA-rituximab final product were prepared as per GMP specifications. The radiolabeling yield from these batches was 93.1 ± 5.8%; these provided final product with radiopharmaceutical yield, purity, and specific activity of 59.2 ± 5.1% (0.9 ± 0.1 GBq of 64Cu), > 95% (by HPLC and radio-thin layer chromatography), and 229.4 ± 43.3 GBq/µmol (or 1.5 ± 0.3 MBq/µg), respectively. The doses passed apyrogenicity and human serum stability specifications, were sterile up to 14 days, and retained > 60% immunoreactivity. In vivo micro-PET/CT mouse images at 24 hours postinjection showed that the tracer targeted the intended sites of human CD20 expression. Thus, we have validated the manufacturing of GMP grade 64Cu-DOTA-rituximab for injection in the clinical setting. PMID:25762106

  4. Prospective evaluation of {sup 68}Ga-DOTA-NOC PET-CT in phaeochromocytoma and paraganglioma: preliminary results from a single centre study

    Naswa, Niraj; Sharma, Punit; Nazar, Aftab Hasan; Agarwal, Krishan Kant; Kumar, Rakesh; Malhotra, Arun; Bal, Chandrasekhar [All India Institute of Medical Sciences, Department of Nuclear Medicine, Ansari Nagar, New Delhi (India); Ammini, Ariachery C. [All India Institute of Medical Sciences, Department of Endocrinology and Metabolism, New Delhi (India)

    2012-03-15

    To evaluate the role of {sup 68}Ga-labelled [1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid]-1-NaI{sup 3}-Octreotide ({sup 68}Ga-DOTA-NOC) whole body positron emission tomography-computed tomography (PET-CT) as a functional imaging approach for phaeochromocytoma and paraganglioma. Thirty-five unrelated patients (Median age-34.4 years; range: 15-71) were evaluated in this prospective study. PET-CT was performed after injection of 132-222 MBq of {sup 68}Ga-DOTA-NOC. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as quantitatively (standardised uptake value-SUVmax). In addition we compared the findings with {sup 131}I Metaiodobenzylguanidine (MIBG) scintigraphy, which was available for 25 patients. Histopathology and/or conventional imaging with biochemical markers were taken as the reference standard. 44 lesions were detected on {sup 68}Ga-DOTA-NOC PET-CT imaging with an additional detection of 12 lesions not previously known, leading to a change in management of 6 patients. Sensitivity, specificity and accuracy were 100%, 85.7%, and 97.1% on a per patient basis and 100%, 85.7% and 98% on per lesion basis, respectively.{sup 131}I MIBG scintigraphy was concordant with {sup 68}Ga-DOTA-NOC PET-CT in 16 patients and false negative in 9 patients. {sup 68}Ga-DOTA-NOC PET-CT is highly sensitive and specific for the detection of phaeochromoctyomas and paragangliomas. It seems better than {sup 131}I MIBG scintigraphy for this purpose. (orig.)

  5. Prospective evaluation of 68Ga-DOTA-NOC PET-CT in phaeochromocytoma and paraganglioma: preliminary results from a single centre study

    To evaluate the role of 68Ga-labelled [1, 4, 7, 10-tetraazacyclododecane-1, 4, 7, 10-tetraacetic acid]-1-NaI3-Octreotide (68Ga-DOTA-NOC) whole body positron emission tomography-computed tomography (PET-CT) as a functional imaging approach for phaeochromocytoma and paraganglioma. Thirty-five unrelated patients (Median age-34.4 years; range: 15-71) were evaluated in this prospective study. PET-CT was performed after injection of 132-222 MBq of 68Ga-DOTA-NOC. Images were evaluated by two experienced nuclear medicine physicians both qualitatively as well as quantitatively (standardised uptake value-SUVmax). In addition we compared the findings with 131I Metaiodobenzylguanidine (MIBG) scintigraphy, which was available for 25 patients. Histopathology and/or conventional imaging with biochemical markers were taken as the reference standard. 44 lesions were detected on 68Ga-DOTA-NOC PET-CT imaging with an additional detection of 12 lesions not previously known, leading to a change in management of 6 patients. Sensitivity, specificity and accuracy were 100%, 85.7%, and 97.1% on a per patient basis and 100%, 85.7% and 98% on per lesion basis, respectively.131I MIBG scintigraphy was concordant with 68Ga-DOTA-NOC PET-CT in 16 patients and false negative in 9 patients. 68Ga-DOTA-NOC PET-CT is highly sensitive and specific for the detection of phaeochromoctyomas and paragangliomas. It seems better than 131I MIBG scintigraphy for this purpose. (orig.)

  6. Chemical Synthesis of Uncommon Natural Bile Acids: The 9α-Hydroxy Derivatives of Chenodeoxycholic and Lithocholic Acids.

    Iida, Takashi; Namegawa, Kazunari; Nakane, Naoya; Iida, Kyoko; Hofmann, Alan Frederick; Omura, Kaoru

    2016-09-01

    The chemical synthesis of the 9α-hydroxy derivatives of chenodeoxycholic and lithocholic acids is reported. For initiating the synthesis of the 9α-hydroxy derivative of chenodeoxycholic acid, cholic acid was used; for the synthesis of the 9α-hydroxy derivative of lithocholic acid, deoxycholic acid was used. The principal reactions involved were (1) decarbonylation of conjugated 12-oxo-Δ(9(11))-derivatives using in situ generated monochloroalane (AlH2Cl) prepared from LiAlH4 and AlCl3, (2) epoxidation of the deoxygenated Δ(9(11))-enes using m-chloroperbenzoic acid catalyzed by 4,4'-thiobis-(6-tert-butyl-3-methylphenol), (3) subsequent Markovnikov 9α-hydroxylation of the Δ(9(11))-enes with AlH2Cl, and (4) selective oxidation of the primary hydroxyl group at C-24 in the resulting 3α,9α,24-triol and 3α,7α,9α,24-tetrol to the corresponding C-24 carboxylic acids using sodium chlorite (NaClO2) in the presence of a catalytic amount of 2,2,6,6-tetramethylpiperidine 1-oxyl free radical (TEMPO) and sodium hypochlorite (NaOCl). The (1)H- and (13)C-NMR spectra are reported. The 3α,7α,9α-trihydroxy-5β-cholan-24-oic acid has been reported to be present in the bile of the Asian bear, and its 7-deoxy derivative is likely to be a bacterial metabolite. These bile acids are now available as authentic reference standards, permitting their identification in vertebrate bile acids. PMID:27319285

  7. Cellular fatty acid composition of marine-derived fungi

    PrabhaDevi; Shridhar, M.P.D.; DeSouza, L.; Naik, C.G.

    sources and mass cultured in the laboratory using organic media. Fatty acids were quantified as methyl esters using gas chromatography (GC), using WICHROM software and data collector. This efficient approach using a computer modelled software program...

  8. Pyrazine Carboxylic Acid Derivatives of Dichlorobis(Cyclopentadienyltitanium(IV

    Satish Chandra Dixit

    2012-07-01

    Full Text Available Reactions of dichlorobis(cyclopentadienyltitanium(IV with pyrazine carboxylic acids viz. 2-pyrazine carboxylic acid (2-PzCH, 5-methyl-2-pyrazine carboxylic acid (MPzCH and 2,3-pyrazine dicarboxylic acid (2,3-PzDCH2 were carried out in different stoichiometric ratios. Complexes of the type Cp2Ti(2-PzCCl , Cp2Ti(2-PzC2 ,Cp2Ti(MPzCCl,Cp2Ti(MPzC2, Cp2Ti(2,3-PzDCHCl and Cp2Ti(2,3-PzDCH2 were obtained. These newly synthesized complexes were characterized on the basis of elemental analyses, electrical conductance, magnetic moment and spectral data.

  9. Pyrazine Carboxylic Acid Derivatives of Dichlorobis(Cyclopentadienyl)titanium(IV)

    Satish Chandra Dixit; Rohit Kumar Singh

    2012-01-01

    Reactions of dichlorobis(cyclopentadienyl)titanium(IV) with pyrazine carboxylic acids viz. 2-pyrazine carboxylic acid (2-PzCH), 5-methyl-2-pyrazine carboxylic acid (MPzCH) and 2,3-pyrazine dicarboxylic acid (2,3-PzDCH2) were carried out in different stoichiometric ratios. Complexes of the type Cp2Ti(2-PzC)Cl , Cp2Ti(2-PzC)2 ,Cp2Ti(MPzC)Cl,Cp2Ti(MPzC)2, Cp2Ti(2,3-PzDCH)Cl and Cp2Ti(2,3-PzDCH)2 were obtained. These newly synthesized complexes were characterized on the basis of elemental analyse...

  10. Co2 chemosorption by functionalized amino acid derivatives

    2015-01-01

    The absorption and desorption behaviour of carbon dioxide (CO2) using a composition comprising an ionic compound comprising a cation [A+] and an anion [B-] is described, wherein the anion [B-] is a mono-amine functionalized amino acid.......The absorption and desorption behaviour of carbon dioxide (CO2) using a composition comprising an ionic compound comprising a cation [A+] and an anion [B-] is described, wherein the anion [B-] is a mono-amine functionalized amino acid....

  11. 13C hyperpolarization of a barbituric acid derivative via parahydrogen induced polarization

    Roth, Meike; Koch, Achim; Kindervater, Petra; Bargon, Joachim; Spiess, Hans Wolfgang; Münnemann, Kerstin

    2010-05-01

    Significant 13C NMR signal enhancement by a factor of 5000 of a barbituric acid derivative (5-methyl-5-propenyl-barbituric acid) via parahydrogen induced polarization is presented. This hyperpolarization is achieved by hydrogenating 5-methyl-5-propargyl-barbituric acid with 98% enriched para-H 2 under elevated temperature and pressure and transferring the initially created 1H hyperpolarization with an INEPT-derived pulse sequence to 13C. The polarization can be selectively transferred to different carbons in the barbituric acid derivative by applying different pulse delays in the INEPT pulse sequence. These results demonstrate the potential of using hyperpolarized barbituric acid derivatives as " active" contrast agents in MRI and visualizing their pharmacokinetics in vivo.

  12. (13)C hyperpolarization of a barbituric acid derivative via parahydrogen induced polarization.

    Roth, Meike; Koch, Achim; Kindervater, Petra; Bargon, Joachim; Spiess, Hans Wolfgang; Münnemann, Kerstin

    2010-05-01

    Significant (13)C NMR signal enhancement by a factor of 5000 of a barbituric acid derivative (5-methyl-5-propenyl-barbituric acid) via parahydrogen induced polarization is presented. This hyperpolarization is achieved by hydrogenating 5-methyl-5-propargyl-barbituric acid with 98% enriched para-H(2) under elevated temperature and pressure and transferring the initially created (1)H hyperpolarization with an INEPT-derived pulse sequence to (13)C. The polarization can be selectively transferred to different carbons in the barbituric acid derivative by applying different pulse delays in the INEPT pulse sequence. These results demonstrate the potential of using hyperpolarized barbituric acid derivatives as "active" contrast agents in MRI and visualizing their pharmacokinetics in vivo. PMID:20207180

  13. Synthesis of Tetrahydrofuran and Tetrahydropyran Derivatives Catalyzed by Tungstophosphoric Acid in Ionic Liquid

    2005-01-01

    Synthesis of tetrahydrofuran and tetrahydropyran derivatives catalyzed by tungstophosphoric acid (H3PW12O4o) were conveniently performed with high yield from the corresponding unsaturated alcohols in ionic liquid. Sufuric acid (H2SO4), trifluoromathanesulfonic acid (TfOH)and p-toluenesulfonic acid (TsOH) were also explored for preparing these products in ionic liquid.The catalysts and ionic liquid can be easily recovered and reused.

  14. Evaluation of phytotoxic and mutagenic effects of some cinnamic acid derivatives using the Triticum test

    JITAREANU, Alexandra; PADUREANU, Silvica; TATARINGA, Gabriela; Tuchilus, Cristina; STANESCU, Ursula

    2013-01-01

    Five cinnamic acid derivatives [cinnamic acid, 2,3-dibromo-3-phenyl-propanoic acid, 2,3-dibromo-3-(3-bromophenyl)-propanoic acid, 2,3-dibromo-3-(4-hydroxy-3-methoxyphenyl)-propanoic acid, and 2,3-dibromo-3-(3-bromo-4-hydroxy-5-methoxyphenyl)-propanoic acid] were found to be active against Staphylococcus aureus ATCC 25923, and their minimal bactericidal concentrations were determined (100 µg/mL). The first step in assessing their toxicological potential was the phytotoxicity and genotoxicity e...

  15. Environmental Method to Determine Dopamine and Ascorbic Acid Simultaneously via Derivative Spectrophotometry

    Ahmed M. El-Zohry; E. Y. Hashem

    2013-01-01

    Many various methods were applied to determine dopamine and ascorbic acid simultaneously using hazardous materials and complex procedures. Derivative absorption spectra can give safely and five sensitive derivative equations that are used for the simultaneous determination of dopamine and ascorbic acid in the UV region, using first and second derivative spectroscopy with high precision at pH value of 9.2. Dopamine and ascorbic acid can be detected in the ranges of 0.375–9.45 mg L−1 and 0.352–...

  16. Fabrication, structure and biological properties of organic acid-derived sol-gel bioactive glasses

    Sol-gel-derived bioactive glasses (BGs) have been developed for bone tissue regeneration. To develop more reliable bone tissue repair systems, it is necessary to control the morphology and surface textures of bioactive glasses. In this study, we prepared bioactive glasses by sol-gel technology using hydrochloride acid, lactic acid, citric acid and acetic acid as hydrolysis catalysts. We studied effects of acids on the morphology and surface textures, apatite-forming bioactivity and cellular response (cellular attachment and proliferation) of BGs. Results showed that the surface morphology, structure, apatite-forming bioactivity and cellular response of BG particles can be controlled by changing acid species. The hydrochloric acid-derived bioactive glass (HBG) and the acetic acid-derived bioactive glass (ABG) present high surface areas and fast apatite-forming rates. Lactic acid- and citric acid-derived bioactive glasses (LBG, CBG) exhibited nanoscale surface morphology, relatively low surface areas and comparable apatite-forming bioactivity. The results of human marrow mesenchymal stem cell (HMSC) culture exhibited that LBG and CBG have an enhanced effect on the cell proliferation, as compared to HBG, ABG and tissue culture plate. This study suggests that sol-gel bioactive glasses with proper surface textures and apatite-forming rate can affect preliminary cellular proliferation.

  17. Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy

    Seregni, E.; Maccauro, M.; Chiesa, C.; Pascali, C.; Lorenzoni, A.; Bogni, A.; Coliva, A.; Bombardieri, E. [Fondazione IRCCS Istituto Nazionale Tumori, Nuclear Medicine, Milan (Italy); Mariani, L.; Vullo, S.Lo [Fondazione IRCCS Istituto Nazionale Tumori, Statistics and Biometry Unit, Milan (Italy); Mazzaferro, V. [Fondazione IRCCS Istituto Nazionale Tumori, Surgery and Liver Transplantation, Milan (Italy); De Braud, F.; Buzzoni, R. [Fondazione IRCCS Istituto Nazionale Tumori, Medical Oncology, Milan (Italy); Milione, M. [Fondazione IRCCS Istituto Nazionale Tumori, Pathology Department, Milan (Italy)

    2014-02-15

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter ({sup 90}Y) and a medium-energy beta/gamma emitter ({sup 177}Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [{sup 177}Lu]DOTA-TATE (5.55 GBq) and [{sup 90}Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [{sup 177}Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment The results of our study indicates that combined [{sup 90}Y]DOTA-TATE and [{sup 177}Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. (orig.)

  18. Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE of neuroendocrine tumours refractory to conventional therapy

    Peptide receptor radionuclide therapy (PRRT) with radiolabelled somatostatin analogues has been demonstrated to be an effective therapeutic option in patients with disseminated neuroendocrine tumours (NET). Treatment with tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE may improve the efficacy of PRRT without increasing the toxicity. In a phase II study we evaluated the feasibility of combined PPRT with a high-energy beta emitter (90Y) and a medium-energy beta/gamma emitter (177Lu) in patients with metastatic NET refractory to conventional therapy. A group of 26 patients with metastatic NET were treated with four therapeutic cycles of alternating [177Lu]DOTA-TATE (5.55 GBq) and [90Y]DOTA-TATE (2.6 GBq). A dosimetric evaluation was carried out after administration of [177Lu]DOTA-TATE to calculate the absorbed doses in healthy organs. The acute and long-term toxicities of repeated treatment were analysed. PRRT efficacy was evaluated according to RECIST. Administration of tandem [90Y]DOTA-TATE and [177Lu]DOTA-TATE induced objective responses in 42.3 % of patients with metastatic NET with a median progression-free survival longer than 24 months. Of patients with pretreatment carcinoid syndrome, 90 % showed a symptomatic response or a reduction in tumour-associated pain. The cumulative biologically effective doses (BED) were below the toxicity limit in the majority of patients, in the absence of renal function impairment The results of our study indicates that combined [90Y]DOTA-TATE and [177Lu]DOTA-TATE therapy is a feasible and effective therapeutic option in NET refractory to conventional therapy. Furthermore, the absence of kidney damage and the evaluated cumulative BEDs suggest that increasing the number of tandem administrations is an interesting approach. (orig.)

  19. Endothelial Differentiation of Human Adipose-Derived Stem Cells on Polyglycolic Acid/Polylactic Acid Mesh

    Meng Deng

    2015-01-01

    Full Text Available Adipose-derived stem cell (ADSC is considered as a cell source potentially useful for angiogenesis in tissue engineering and regenerative medicine. This study investigated the growth and endothelial differentiation of human ADSCs on polyglycolic acid/polylactic acid (PGA/PLA mesh compared to 2D plastic. Cell adhesion, viability, and distribution of hADSCs on PGA/PLA mesh were observed by CM-Dil labeling, live/dead staining, and SEM examination while endothelial differentiation was evaluated by flow cytometry, Ac-LDL/UEA-1 uptake assay, immunofluorescence stainings, and gene expression analysis of endothelial related markers. Results showed hADSCs gained a mature endothelial phenotype with a positive ratio of 21.4 ± 3.7% for CD31+/CD34− when induced in 3D mesh after 21 days, which was further verified by the expressions of a comprehensive range of endothelial related markers, whereas hADSCs in 2D induced and 2D/3D noninduced groups all failed to differentiate into endothelial cells. Moreover, compared to 2D groups, the expression for α-SMA was markedly suppressed in 3D cultured hADSCs. This study first demonstrated the endothelial differentiation of hADSCs on the PGA/PLA mesh and pointed out the synergistic effect of PGA/PLA 3D culture and growth factors on the acquisition of mature characteristic endothelial phenotype. We believed this study would be the initial step towards the generation of prevascularized tissue engineered constructs.

  20. Radiochemical investigations of 177Lu-DOTA-8-Aoc-BBN[7-14]NH2: an in vitro/in vivo assessment of the targeting ability of this new radiopharmaceutical for PC-3 human prostate cancer cells

    Bombesin (BBN), a 14 amino acid peptide, is an analogue of human gastrin releasing peptide (GRP) that binds to GRP receptors (GRPr) with high affinity and specificity. The GRPr is over expressed on a variety of human cancer cells including prostate, breast, lung, and pancreatic cancers. The specific aim of this study was to identify a BBN analogue that can be radiolabeled with 177Lu and maintains high specificity for GRPr positive prostate cancer tumors in vivo. A preselected synthetic sequence via solid phase peptide synthesis (SPPS) was designed to produce a DOTA-BBN (DOTA 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid) conjugate with the following general structure: DOTA-X-Q-W-A-V-G-H-L-M-(NH2), where the spacer group, X = ω-NH2(CH2)7COOH (8-Aoc). The BBN-construct was purified by reversed phase-HPLC (RP-HPLC). Electrospray Mass Spectrometry (ES-MS) was used to characterize both metallated and non-metallated BBN-conjugates. The new DOTA-conjugate was metallated with 177Lu(III)Cl3 or non-radioactive Lu(III)Cl3. The 177Lu(III)- and non-radiolabeled Lu(III)-conjugates exhibit the same retention times under identical RP-HPLC conditions. The 177Lu-DOTA-8-Aoc-BBN[7-14]NH2 conjugate was found to exhibit optimal pharmacokinetic properties in CF-1 normal mice. In vitro and in vivo models demonstrated the ability of the 177Lu-DOTA-8-Aoc-BBN[7-14]NH2 conjugate to specifically target GRP receptors expressed on PC-3 human prostate cancer cells

  1. Formation of Amino Acid Derived Cheese Flavour Compounds

    Smit, B.A.

    2004-01-01

    Lactic acid bacteria (LAB), among them Lactococcus lactis, are often used for the fermentation of milk into various products, such as cheeses. For their growth and maintenance LAB metabolise milk sugar, protein and fat into various low molecular compounds, which sometimes have strong flavour charact

  2. Population Genetic Structure of Legionella pneumophila Inferred from RNA Polymerase Gene (rpoB) and DotA Gene (dotA) Sequences

    Ko, Kwan Soo; Lee, Hae Kyung; Park, Mi-Yeoun; Park, Man-Suk; Lee, Keun-Hwa; Woo, So-Yon; Yun, Yeo-Jun; Kook, Yoon-Hoh

    2002-01-01

    The population structure of Legionella pneumophila was studied by using partial RNA polymerase gene (rpoB) and DotA gene (dotA) sequences. Trees inferred from rpoB sequences showed that two subspecies of L. pneumophila, Legionella pneumophila subsp. pneumophila and Legionella pneumophila subsp. fraseri, were clearly separated genetically. In both rpoB and dotA trees, 79 Korean isolates used in this study constituted six clonal populations, four of which (designated subgroups P-I to P-IV) were...

  3. Syntheses,characteristics,and fluorescence properties of complexes of europium with benzoic acid and its derivatives

    ZHOU Zhongcheng; SHU Wangen; RUAN Jianming; HUANG Boyun; LIU Younian

    2004-01-01

    The binary complexes of europium with benzoic acid and its derivatives (phthalic acid, m-phthalic acid,o-aminobenzoic acid, salicylic acid, and sulfosalicylic acid) were synthesized and their compositions were identified by elemental analyses. UV and IR of the complexes have been investigated. The UV spectra indicated that the complexes' ultraviolet absorption were mainly the ligands' absorption. The IR spectra showed that the IR spectra of complexes are different from those of free ligands. The fluorescence properties of them were investigated by using luminescence spectroscopy, the results showed that only three complexes appear as better luminescence, they were Eu-benzoic acid,Eu-m-phthalic acid and Eu-phthalic acid, while the others exhibited the ligands' wideband emission.

  4. Preclinical evaluation of [ 111 In]-DOTA-trastuzumab for clinical trials

    Behrouz Alirezapour

    2014-01-01

    Full Text Available Context: Herceptin and its fragments have been radiolabeled and used in the imaging of human epidermal growth factor receptor 2 (HER2/neu-positive tumors and development of diagnostic kits is of great importance in radiopharmacy. Aims: In this study, 111 In-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-trastuzumab ( 111 In-DOTA-trastuzumab was successively prepared and evaluated for ultimate use in the HER2 antigen imaging in oncology. Settings and Design: The conjugate was prepared, labeled and evaluated using in vitro (radioimmunoassay [RIA], enzyme-linked immunosorbent assay (ELISA, stability, binding, internalization/in vivo (bio-distribution, single-photon emission computed tomography [SPECT] experiments. Materials and Methods: 111 In-DOTA-trastuzumab was prepared followed by determination of radiochemical purity (RCP, integrity of protein, immunoreactivity of radiolabeled antibody with HER2/neu antigen (by SkBr3 cell line binding and RIA methods were determined followed by stability tests, internalization studies and the tissue bio-distribution determination in wild-type rats as well as SPECT imaging in SkBr3-bearing mice. Statistical Analysis Used: All values were expressed as mean ± standard deviation (mean ± SD and the data were compared using Student′s t-test. Statistical significance was defined as P 95 ± 0.5%, S.A. 5.3 μCi/μg with the average number of chelators per antibody of 6:1 showing significant immune-reactivity retention using ELISA. In vitro stability was >90% in phosphate buffered saline and 80 ± 0.5% in serum over 48 h. Cell binding was significant (>0.79. In vitro internalization reached up to %12-13 in 10 h. Significant tumor uptake was observed. Conclusions: In vitro and in vivo/SPECT imaging in SkBr3-bearing mice demonstrated that 111 In-DOTA-trastuzumab is a potential compound for molecular imaging of SPECT for diagnosis and follow-up of HER2 expression in oncology.

  5. Formation of Amino Acid Derived Cheese Flavour Compounds

    Smit, B.A.

    2004-01-01

    Lactic acid bacteria (LAB), among them Lactococcus lactis, are often used for the fermentation of milk into various products, such as cheeses. For their growth and maintenance LAB metabolise milk sugar, protein and fat into various low molecular compounds, which sometimes have strong flavour characteristics. This thesis focuses on the production of one class of these compounds as a model system: aldehydes, in particular the key-flavour compounds 3-methylbutanal and 2-methyl propanal, which ar...

  6. Silica with immobilized phosphinic acid-derivative for uranium extraction.

    Budnyak, Tetyana M; Strizhak, Alexander V; Gładysz-Płaska, Agnieszka; Sternik, Dariusz; Komarov, Igor V; Kołodyńska, Dorota; Majdan, Marek; Tertykh, Valentin А

    2016-08-15

    A novel adsorbent benzoimidazol-2-yl-phenylphosphinic acid/aminosilica adsorbent (BImPhP(O)(OH)/SiO2NH2) was prepared by carbonyldiimidazole-mediated coupling of aminosilica with 1-carboxymethylbenzoimidazol-2-yl-phenylphosphinic acid. It was obtained through direct phosphorylation of 1-cyanomethylbenzoimidazole by phenylphosphonic dichloride followed by basic hydrolysis of the nitrile. The obtained sorbent was well characterized by physicochemical methods, such as differential scanning calorimetry-mass spectrometry (DSC-MS), surface area and pore distribution analysis (ASAP), scanning electron microscopy (SEM), X-ray photoelectron (XPS) and Fourier transform infrared (FTIR) spectroscopies. The adsorption behavior of the sorbent and initial silica gel as well as aminosilica gel with respect to uranium(VI) from the aqueous media has been studied under varying operating conditions of pH, concentration of uranium(VI), contact time, and desorption in different media. The synthesized material was found to show an increase in adsorption activity with respect to uranyl ions in comparison with the initial compounds. In particular, the highest adsorption capacity for the obtained modified silica was found at the neutral pH, where one gram of the adsorbent can extract 176mg of uranium. Under the same conditions the aminosilica extracts 166mg/g, and the silica - 144mg/g of uranium. In the acidic medium, which is common for uranium nuclear wastes, the synthesized adsorbent extracts 27mg/g, the aminosilica - 16mg/g, and the silica - 14mg/g of uranium. It was found that 15% of uranium ions leached from the prepared material in acidic solutions, while 4% of uranium can be removed in a phosphate solution. PMID:27177215

  7. Palladium-Catalyzed C–C Bond Formations via Activation of Carboxylic Acids and Their Derivatives

    Song, Bingrui

    2013-01-01

    Applications of carboxylic acids and their derivatives in transition metal-catalyzed cross-coupling reactions regio-selectively forming Csp3-Csp2, and Csp2-Csp2 bonds were explored in this thesis. Several important organic building blocks such as aryl acetates, diaryl acetates, imines, ketones, biaryls, styrenes and polysubstituted alkenes were successfully accessed from carboxylic acids and their derivatives by the means of C–H activation and decarboxylative cross-couplings. An efficient ...

  8. Anti-inflammatory pro-resolving derivatives of omega-3 and omega-6 polyunsaturated fatty acids

    Jerzy Z. Nowak

    2010-01-01

    Inflammation is a physiological defense reaction of living tissues to injury or infection. An array of mediators, including those derived from omega-6 (ω6) polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) e.g. prostaglandins and leukotrienes, promote the inflammatory response. Acute inflammation has several programmed fates, including complete resolution or progression to chronic inflammation, scarring, and eventual loss of tissue function. Studies on AA-derived proinflammat...

  9. Antitrypanosomal Activity of Novel Benzaldehyde-Thiosemicarbazone Derivatives from Kaurenoic Acid

    2011-01-01

    A series of new thiosemicarbazones derived from natural diterpene kaurenoic acid were synthesized and tested against the epimastigote forms of Trypanosoma cruzi to evaluate their antitrypanosomal potential. Seven of the synthesized thiosemicarbazones were more active than kaurenoic acid with IC50 values between 2-24.0 mM. The o-nitro-benzaldehyde-thiosemicarbazone derivative was the most active compound with IC50 of 2.0 mM. The results show that the structural modifications accomplished enhan...

  10. Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives

    Lesyk R. B.; Kaminskyy D. V.

    2010-01-01

    The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR) aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program). Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to...

  11. An amine-derivatized, DOTA-loaded polymeric support for Fmoc Solid Phase Peptide Synthesis

    Yoo, Byunghee; Sheth, Vipul R.; Pagel, Mark D.

    2009-01-01

    An amine-derivatized DOTA has been used to modify the surface of a polymeric support for conventional Solid Phase Peptide Synthesis (SPPS) following standard Fmoc chemistry methods. This methodology was used to synthesize a peptide-DOTA conjugate that was demonstrated to be a PARACEST MRI contrast agent. Therefore, this synthesis methodology can facilitate Fmoc SPPS of molecular imaging contrast agents.

  12. CEC enantioseparations of carboxylic acids on silica-based monoliths modified with ergot alkaloid derivative

    Messina, A.; Moroni, S.; Flieger, Miroslav; Sinibaldi, M.; Ursini, O.

    2009-01-01

    Roč. 30, č. 16 (2009), s. 2890-2896. ISSN 0173-0835 Institutional research plan: CEZ:AV0Z50200510 Keywords : 2-Aryloxypropionic acids * chiral separations * dansyl amino acid derivatives Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 3.077, year: 2009

  13. Modification of oligo-Ricinoleic Acid and Its Derivatives with 10-Undecenoic Acid via Lipase-Catalyzed Esterification

    M. Claudia Montiel

    2012-04-01

    Full Text Available Lipases were employed under solvent-free conditions to conjugate oligo-ricinoleic acid derivatives with 10-undecenoic acid, to incorporate a reactive terminal double bond into the resultant product. First, undecenoic acid was covalently attached to oligo-ricinoleic acid using immobilized Candida antarctica lipase (CAL at a 30% yield. Thirty percent conversion also occurred for CAL-catalyzed esterification between undecenoic acid and biocatalytically-prepared polyglycerol polyricinoleate (PGPR, with attachment of undecenoic acid occurring primarily at free hydroxyls of the polyglycerol moiety. The synthesis of oligo-ricinoleyl-, undecenoyl- structured triacylglycerols comprised two steps. The first step, the 1,3-selective lipase-catalyzed interesterification of castor oil with undecenoic acid, occurred successfully. The second step, the CAL-catalyzed reaction between ricinoleyl-, undecenoyl structured TAG and ricinoleic acid, yielded approximately 10% of the desired structured triacylglycerols (TAG; however, a significant portion of the ricinoleic acid underwent self-polymerization as a side-reaction. The employment of gel permeation chromatography, normal phase HPLC, NMR, and acid value measurements was effective for characterizing the reaction pathways and products that formed.

  14. Merocyanine-type dyes from barbituric acid derivatives

    Rezende, Marcos Caroli; Campodonico, Paola; Abuin, Elsa; Kossanyi, Jean

    2001-05-01

    The preparation and the solvatochromic behavior of two dyes, obtained by condensation of N, N'-dimethylbarbituric acid with dimethylaminobenzaldehyde and with 4,4'-bis( N, N-dimethylamino)benzophenone (Michler's ketone) are described. The latter dye is rather sensitive to the polarity of the medium, and in particular, to the hydrogen-bond-donor ability of protic solvents. The solvatochromism of both compounds is discussed in terms of the π* and ET(30) solvent polarity scales and their differences in behavior interpreted with the aid of semiempirical calculations.

  15. Benzothiazole incorporated barbituric acid derivatives: synthesis and anticonvulsant screening.

    Siddiqui, Nadeem; Ahsan, Waquar

    2009-08-01

    A series of 1-(6-substituted-1,3-benzothiazol-2-yl)-3-(substituted phenyl)hexahydro-2,4,6-pyrimidinetriones 4a-t were synthesized starting from substituted anilines. These compounds contained two active anticonvulsant pharmacophores, benzothiazole and barbituric acid. Structures of the compounds were confirmed on the basis of different spectroscopic techniques. All the compounds were evaluated for their anticonvulsant activity. Three compounds 4c, 4d, and 4s showed promising anticonvulsant activities in Maximal Electroshock Seizure test (MES) and subcutaneous pentylenetetrazole test (scPTZ). They also displayed a wide safety profile when tested for the minimal motor impairment test. PMID:19565603

  16. MR study of acute myocardial infarction with injection of Gd-DOTA (Fifteen patients)

    We studied 15 patients 4 to 8 days after myocardial infarction by using ECG gated MR before and after administration of 0.2 mmol/kg Gd-DOTA. The diagnosis in each patient was confirmed by electrocardiographic criteria, elevated levels of fractionated creatine kinase (CK) isoenzyme, thallium scintigraphy, ventriculography and coronarography. T1-weighted, spin-echo images, were obtained before and immediately after injection of Gd-DOTA and were repeated 15 min later. The site of infarction was visualized in 10 patients as an area of high signal intensity after the injection of Gd-DOTA. Contrast between normal and infarcted myocardium was greatest 15 min after injection. Three patients were excluded because of failure to acquire adequate MR studies. In 2 other patients the infarct was not detected. Before injection of Gd-DOTA, only 2 infarcts were detected. These results suggest that Gd-DOTA can improve MR visualization and detection of acute myocardial infarction

  17. MR study of acute myocardial infarction with injection of Gd-DOTA (Fifteen patients)

    We studied 15 patients 4 to 8 days after myocardial infarction by using ECG gated MR before and after administration of 0.2 mmol/kg Gd-DOTA. The diagnosis in each patient was confirmed by electrocardiographic criteria, elevated levels of fractionated creatine kinase (CK) isoenzyme, thallium scintigraphy, ventriculography and coronarography. T1-weighted, spin-echo images, were obtained before and immediately after injection of Gd-DOTA and were repeated 15 min later. The site of infarction was visualized in 10 patients as an area of high signal intensity after the injection of Gd-DOTA. Contrast between normal and infarcted myocardium was greatest 15 min after injection. Three patients were excluded because of failure to acquire adequate MR studies. In 2 other patients, the infarct were not detected. Before injection of Gd-DOTA, only 2 infarcts were detected. These results suggest that Gd-DOTA can improve MR visualization and detection of acute myocardial infarction

  18. Green Synthesis and Urease Inhibitory Activity of Spiro-Pyrimidinethiones/Spiro-Pyrimidinones-Barbituric Acid Derivatives

    Mohammadi Ziarani, Ghodsi; Asadi, Shima; Faramarzi, Sakineh; Amanlou, Massoud

    2015-01-01

    Sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) with pore size 6 nm as an efficient heterogeneous nanoporous solid acid catalyst exhibited good catalytic activity in the Biginelli-like reaction in the synthesis of spiroheterobicyclic rings with good yield and good recyclability. Spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives were synthesized in a simple and efficient method using the one-pot three-component reaction of a cyclic 1,3- dicarbonyl compounds (barbituric ...

  19. Two New Cholic Acid Derivatives from the Marine Ascidian-Associated Bacterium Hasllibacter halocynthiae

    Sung Hun Kim

    2012-10-01

    Full Text Available The investigation of secondary metabolites in liquid cultures of a recently discovered marine bacterium, Hasllibacter halocynthiae strain KME 002T, led to the isolation of two new cholic acid derivatives. The structures of these compounds were determined to be 3,3,12-trihydroxy-7-ketocholanic acid (1 and 3,3,12-trihydroxy-7-deoxycholanic acid (2 through HRFABMS and NMR data analyses.

  20. Acyl Meldrum's acid derivatives: application in organic synthesis

    This review is focused on an important class of Meldrum's acid derivatives commonly known as acyl Meldrum's acids. The preparation methods of these compounds are considered including the recently proposed and rather rarely used ones. The chemical properties of acyl Meldrum's acids are described in detail, including thermal stability and reactions with various nucleophiles. The possible mechanisms of these transformations are analyzed. The bibliography includes 134 references

  1. p-Nitrobenzoic acid promoted synthesis of 1,5-benzodiazepine derivatives

    Varala, Ravi; Enugala, Ramu; Adapa, Srinivas R. [Indian Institute of Chemical Technology, Hyderabad (India)]. E-mail: rvarala_iict@yahoo.co.in

    2007-03-15

    p-Nitrobenzoic acid was found to be the versatile Bronsted organic acid promoter among the carboxylic acids tested for the preparation of 1,5-benzodiazepine derivatives from a wide range of substituted o-phenylenediamines and ketones. The corresponding products were obtained in good isolated yields (62-92%) under mild conditions using acetonitrile as solvent at ambient temperature. Further, the reagent could be easily recovered and reused. (author00.

  2. Synthesis and anti-tumor activity of all-trans retinoic acid derivatives

    Juan Shen; Jing Bo Shi; Fei Hu Chen; Yuan Wang; Jing Jing Ruan; Yua Huang

    2009-01-01

    A series of retinoate and retinamide derivatives were designed, synthesized, and their anti-tumor activities were investigated in NB4 by MTT and flow cytometry assays (FCM). All compounds showed cytotoxicity, especially compounds 1a and 1d exhibited a higher cytotoxicity than other derivatives and all-traus retinoic acid (ATRA). Furthermore, compound ld could induce NB4 cell lines differentiation efficiently.

  3. Corrosion inhibition of steel in sulphuric acid by pyrrolidine derivatives

    Novel corrosion inhibitors, namely 1-{2-[(2-hydroxyethyl)thio]ethyl}pyrrolidin-2-one (P5) and {[2-(2-oxopyrrolidin-1-yl)ethyl]thio}acetic acid (P4), were synthesised and tested as corrosion inhibitors for steel in 0.5 M H2SO4. The effects of P4 and P5 are also compared to their initial reactants 1-vinylpyrrolidin-2-one (P1), 2-mercaptoethanol (P2) and mercaptoacetic acid (P3). The study was carried out by weight loss measurements, potentiodynamic polarisation, linear polarisation resistance (R p) and electrochemical impedance spectroscopy (EIS) methods. The inhibition efficiency increases with the concentration of P5 to attain 89% at 5 x 10-3 M. We note good agreement between the various methods explored. Polarisation measurements show also that the pyrrolidones act essentially as cathodic inhibitors. The cathodic curves indicate that the reduction of proton at the steel surface is an activating mechanism. P4 and P5 adsorb on the steel surface according to Langmuir adsorption model. Effect of temperature is also studied in the 298-353 K range. Efficiency is explained by the theoretical studies

  4. The developmental toxicity of perfluoroalkyl acids and their derivatives

    Perfluoroalkyl acids such as perfluorooctane sulfonate (PFOS) and perfluorooctanoic acid (PFOA) have applications in numerous industrial and consumer products. Although the toxicology of some of these compounds has been investigated in the past, the widespread prevalence of PFOS and PFOA in humans, as demonstrated in recent bio-monitoring studies, has drawn considerable interest from the public and regulatory agencies as well as renewed efforts to better understand the hazards that may be inherent in these compounds. This review provides a brief overview of the perfluoroalkyl chemicals and a summary of the available information on the developmental toxicity of the eight-carbon compounds, PFOS and PFOA. Although the teratological potentials of some of these chemicals had been studied in the past and the findings were generally unremarkable, results from recent postnatal studies on developmental and reproductive indices have prompted consideration of their relevance to human health risk. Based on current understanding of the developmental effects of PFOS and PFOA in rodents, several avenues of research are suggested that would further support the risk assessment of these perfluorinated organic chemicals

  5. Photosensitization of Nanocrystalline TiO2 Electrode Modifiedwith C60 Carboxylic Acid Derivatives

    张文; 史亚茹; 甘良兵; 黄春辉; 王艳琴; 虎民

    2001-01-01

    C60 carboxylic acid derivatives can be readily adsorbed on the surface of nanocrystalline TiO2 films act as charge-transfer sensitizer. The electron transport from TiO2 to the C60 derivatives results in the generation of the cathodic photocurrent. The short-circuit photocurrent of a C60 tetracarboxylic acid is 0.45 μA/cm2 under 464 um light illumination. The photoelectric behaviour of ITO electrodes modified by the same C60 carboxylic acids is different from that of the modified TiO2 electrodes, and shows anodic photocurrent.

  6. Percutaneous absorption of nicotinic acid derivatives in vitro.

    Dal Pozzo, A; Donzelli, G; Liggeri, E; Rodriguez, L

    1991-01-01

    The permeation rates through isolated epidermis of a homologous series of glycol, polyglycol, and alkyl esters of nicotinic acid were measured in vitro in a two-compartment diffusion cell assembly, using an isotonic buffered solution as the receiving phase. The esters were applied from aqueous solutions and also as the pure liquids. The results were consistent with those reported by other using compounds of equal or different structures either in vitro or in vivo. The experiments are compared in terms of partition equilibrium between vehicle and tissue and distribution from tissue to the receiving phase. It was demonstrated that the plateau observed in skin permeabilities of the compounds beyond a certain degree of lipophilicity is the result of the effect of water when used as the vehicle in the laboratory models. PMID:2013851

  7. Synthesis of tyrosine derivatives containing boric acid moiety

    Kitazawa, M.; Yoshino, Kazuo [Shinshu Univ., Faculty of Science, Matsumoto, Nagano (Japan); Kimura, M.

    1998-12-01

    While p-boronophenylalanine (p-BPA) is known as a useful pharmaceutical for Boron Neutron Capture Therapy (BNCT), it is also reported that the boron content after it is accumulated in melanomas decreases gradually with time. 2-hydroxy-5-(2' carboxy-2'-aminoethyl) phenyl boric acid (HBPA) is suggested for alternative candidate to be used, as the compound (HBPA) resembles more in chemical nature to tyrosine and is more difficult to be oxidized by tyrosinase than p-BPA. The authors tried to synthesize HBPA via isocyanoethylacetate, employing 1-bromo-2-methoxy-5-methylbenzene as a starting material. The structure of the synthesized compounds at each steps in the course of the scheme was determined using {sup 1}H, {sup 13}C and {sup 11}B NMR spectrometer. (S. Ohno)

  8. Development of novel radiogallium-labeled bone imaging agents using oligo-aspartic acid peptides as carriers.

    Kazuma Ogawa

    Full Text Available (68Ga (T 1/2 = 68 min, a generator-produced nuclide has great potential as a radionuclide for clinical positron emission tomography (PET. Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting (68Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Aspn (n = 2, 5, 8, 11, or 14 with easy-to-handle (67Ga, with the previously described (67Ga-DOTA complex conjugated bisphosphonate, (67Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Aspn by a Fmoc-based solid-phase method, complexes were formed with (67Ga, resulting in (67Ga-DOTA-(Aspn with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of (67Ga-DOTA-(Aspn increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, (67Ga-DOTA-(Asp8, (67Ga-DOTA-(Asp11, and (67Ga-DOTA-(Asp14 showed high accumulation in bone (10.5 ± 1.5, 15.1 ± 2.6, and 12.8 ± 1.7% ID/g, respectively but were barely observed in other tissues at 60 min after injection. Although bone accumulation of (67Ga-DOTA-(Aspn was lower than that of (67Ga-DOTA-Bn-SCN-HBP, blood clearance of (67Ga-DOTA-(Aspn was more rapid. Accordingly, the bone/blood ratios of (67Ga-DOTA-(Asp11 and (67Ga-DOTA-(Asp14 were comparable with those of (67Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of (68Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases.

  9. Hyperpolarized 89Y NMR spectroscopic detection of yttrium ion and DOTA macrocyclic ligand complexation: pH dependence and Y-DOTA intermediates

    Ferguson, Sarah; Kiswandhi, Andhika; Niedbalski, Peter; Parish, Christopher; Kovacs, Zoltan; Lumata, Lloyd

    Dissolution dynamic nuclear polarization (DNP) is a rapidly emerging physics technique used to enhance the signal strength in nuclear magnetic resonance (NMR) and imaging (MRI) experiments for nuclear spins such as yttrium-89 by >10,000-fold. One of the most common and stable MRI contrast agents used in the clinic is Gd-DOTA. In this work, we have investigated the binding of the yttrium and DOTA ligand as a model for complexation of Gd ion and DOTA ligand. The macrocyclic ligand DOTA is special because its complexation with lanthanide ions such as Gd3+ or Y3+ is highly pH dependent. Using this physics technology, we have tracked the complexation kinetics of hyperpolarized Y-triflate and DOTA ligand in real-time and detected the Y-DOTA intermediates. Different kinds of buffers were used (lactate, acetate, citrate, oxalate) and the pseudo-first order complexation kinetic calculations will be discussed. The authors would like to acknowledge the support by US Dept of Defense Award No. W81XWH-14-1-0048 and Robert A. Welch Foundation Grant No. AT-1877.

  10. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.§

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-01-01

    Abstract Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data (1H-, 13C-NMR, MS, optical rotation). PMID:26171328

  11. Hydroxycinnamic Acid Derivatives Obtained from a Commercial Crataegus Extract and from Authentic Crataegus spp.

    Kuczkowiak, Ulrich; Petereit, Frank; Nahrstedt, Adolf

    2014-12-01

    Eleven hydroxycinnamic acid derivatives were isolated from a 70% methanolic Crataegus extract (Crataegi folium cum flore) and partly verified and quantified for individual Crataegus species (C. laevigata, C. monogyna, C. nigra, C. pentagyna) by HPLC: 3-O-(E)-p-coumaroylquinic acid (1), 5-O-(E)-p-coumaroyl-quinic acid (2), 4-O-(E)-p-coumaroylquinic acid (3), 3-O-(E)-caffeoylquinic acid (4), 4-O-(E)-caffeoylquinic acid (5), 5-O-(E)-caffeoylquinic acid (6), 3,5-di-O-(E)-caffeoylquinic acid (7), 4,5-di-O-(E)-caffeoylquinic acid (8), (-)-2-O-(E)-caffeoyl-L-threonic acid (9), (-)-4-O-(E)-caffeoyl-L-threonic acid (10), and (-)-4-O-(E)-p-coumaroyl-L-threonic acid (11). Further, (-)-2-O-(E)-caffeoyl-D-malic acid (12) was isolated from C. submollis and also identified for C. pentagyna and C. nigra by co-chromatography. The isolates 10 and 11 were not found in the authentic fresh specimen, indicating that they may be formed during extraction by acyl migration from the 2-O-acylderivatives. Also, 9 and 11 are described here for the first time. All structures were assigned on the basis of their spectroscopic data ((1)H-, (13)C-NMR, MS, optical rotation). PMID:26171328

  12. Preclinical study of radioiodinated glucose-Tyr3-octreotate: Comparison with 111In-DOTA-Tyr3-octreotate

    Full text: Targeted radionuclide imaging and treatment are based upon the interaction of radioligands with receptors in the target tissue (namely high density receptor specific tumours). As receptors for somatostatin (mainly somatostatin receptor subtype-2 /sstr2/) are over-expressed in several human tumours of endocrine origin, a number of radiolabeled somatostatin analogs have been recently introduced as the vectors for targeted imaging and therapy; commercially available 111In-DTPA-octreotide being a gold standard in this field. Several publications demonstrate that a substitution of Tyr instead of Phe in the peptide position 3 and oxidation of carboxyl end of octreotide significantly increased the affinity of the peptide to sstr2. More recently it has been shown that NH2-terminal carbohydration leads to a further improvement of the peptide receptor affinity and its retention in the tumour. In this study we present preclinical analysis of distribution profile and elimination pathways of radioiodinated glucose-Tyr3-octreotate (125I-gluc-TOCA) in comparison with that of another promising targeted radiopharmaceutical, namely 111In-DOTA-Tyr3-octreotate (111In- DOTA-TOCA). Gluc-TOCA was radioiodinated using chloramine-T method. For radiolabeling of DOTA-TOCA with radiometal, to 200 μl of 0.4 M acetate buffer with 0.24 M gentisic acid pH 5, 10μl of peptide solution in 0.1% TFA (1mg/ml) were added together with 0.5-1 mCi of 111InCl3 in 0.04 M HCl. Reaction mixture was heated 25 minutes to 90-95 deg. C. Pharmacokinetic studies were performed on male Wistar rats. Results confirmed that specific internalization of 125I-gluc-TOCA by sstr2 - expressing AR423 rat pancreatic carcinoma cells in vitro was about twice of that for 111In-DOTA-TOCA. In rats, 125I-gluc-TOCA exhibited prolonged plasma clearance in comparison with the other peptide. Slower decrease of plasma radioactivity after 125I-gluc-TOCA was due to its higher lipophilicity and thus higher plasma protein binding

  13. Metabolic Engineering of Yeast to Produce Fatty Acid-derived Biofuels: Bottlenecks and Solutions

    Jiayuan eSheng

    2015-06-01

    Full Text Available Fatty acid-derived biofuels can be a better solution than bioethanol to replace petroleum fuel, since they have similar energy content and combustion properties as current transportation fuels. The environmentally friendly microbial fermentation process has been used to synthesize advanced biofuels from renewable feedstock. Due to their robustness as well as the high tolerance to fermentation inhibitors and phage contamination, yeast strains such as Saccharomyces cerevisiae and Yarrowia lipolytica have attracted tremendous attention in recent studies regarding the production of fatty acid-derived biofuels, including fatty acids, fatty acid ethyl esters, fatty alcohols, and fatty alkanes. However, the native yeast strains cannot produce fatty acids and fatty acid-derived biofuels in large quantities. To this end, we have summarized recent publications in this review on metabolic engineering of yeast strains to improve the production of fatty acid-derived biofuels, identified the bottlenecks that limit the productivity of biofuels, and categorized the appropriate approaches to overcome these obstacles.

  14. The tumour sink effect on the biodistribution of 68Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of 68Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on 68Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of 68Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  15. The tumour sink effect on the biodistribution of {sup 68}Ga-DOTA-octreotate: implications for peptide receptor radionuclide therapy

    Beauregard, Jean-Mathieu [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia); Centre hospitalier universitaire de Quebec and Laval University, Molecular Imaging Research Group, Medical Imaging Department, Quebec City, QC (Canada); Hofman, Michael S.; Kong, Grace; Hicks, Rodney J. [Peter MacCallum Cancer Centre and University of Melbourne, Centre for Cancer Imaging, Melbourne (Australia)

    2012-01-15

    Tumour sequestration of radiotracer may lead to decreased bioavailability in healthy tissue resulting in lower absorbed radiation dose to critical organs. This study aims to assess the impact of disease burden, body habitus and urinary excretion on the biodistribution of {sup 68}Ga-DOTA-octreotate. Ten patients with highly varied burden of somatostatin receptor-positive neuroendocrine tumour on {sup 68}Ga-DOTA-octreotate positron emission tomography (PET)/CT were selected. Volumes of interest were drawn to derive the average uptake of renal parenchyma, spleen and body background, as well as to compute the fraction of injected activity sequestered in tumour and excreted in urine. Uptake values were assessed for correlation with tumour sequestration, weight, lean body weight, body surface area and urinary excretion. There was a trend for tumour sequestration, body habitus and urinary excretion to inversely influence all healthy tissue uptake values. In particular, renal uptake, splenic intensity and background soft tissue activity were all significantly correlated to composite factors combining tumour sequestration with body habitus and renal excretion. When combined with body habitus index or a body habitus index and renal excretion, tumour sequestration was strongly and significantly correlated inversely with renal uptake. Our results suggest that tumour sequestration of {sup 68}Ga-DOTA-octreotate is a major factor leading to a sink effect that decreases activity concentration in healthy organs such as the kidney. However, body habitus and renal function also influence tissue biodistribution, in a synergistic fashion. Compared with a fixed-dose peptide receptor radionuclide therapy protocol, an adjusted-dose regimen tailored to tumour burden, body habitus and renal function may allow greater radiation dose to individual lesions without substantially adding to toxicity in normal tissues. (orig.)

  16. Amifostine protects rat kidneys during peptide receptor radionuclide therapy with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate

    Rolleman, Edgar J.; Forrer, Flavio; Bernard, Bert; Bijster, Magda; Valkema, Roelf; Krenning, Eric P.; Jong, Marion de [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Vermeij, Marcel [Erasmus MC, Department of Pathology, Rotterdam (Netherlands)

    2007-05-15

    In peptide receptor radionuclide therapy (PRRT) using radiolabelled somatostatin analogues, the kidneys are the major dose-limiting organs, because of tubular reabsorption and retention of radioactivity. Preventing renal uptake or toxicity will allow for higher tumour radiation doses. We tested the cytoprotective drug amifostine, which selectively protects healthy tissue during chemo- and radiotherapy, for its renoprotective capacities after PRRT with high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Male Lewis rats were injected with 278 or 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate to create renal damage and were followed up for 130 days. For renoprotection, rats received either amifostine or co-injection with lysine. Kidneys, blood and urine were collected for toxicity measurements. At 130 days after PRRT, a single-photon emission computed tomography (SPECT) scan was performed to quantify tubular uptake of {sup 99m}Tc-dimercaptosuccinic acid (DMSA), a measure of tubular function. Treatment with 555 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate resulted in body weight loss, elevated creatinine and proteinuria. Amifostine and lysine treatment significantly prevented this rise in creatinine and the level of proteinuria, but did not improve the histological damage. In contrast, after 278 MBq [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate, creatinine values were slightly, but not significantly, elevated compared with the control rats. Proteinuria and histological damage were different from controls and were significantly improved by amifostine treatment. Quantification of {sup 99m}Tc-DMSA SPECT scintigrams at 130 days after [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate therapy correlated well with 1/creatinine (r {sup 2} = 0.772, p < 0.001). Amifostine and lysine effectively decreased functional renal damage caused by high-dose [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Besides lysine, amifostine might be used in clinical PRRT as well

  17. Irbic acid, a dicaffeoylquinic acid derivative from Centella asiatica cell cultures.

    Antognoni, Fabiana; Perellino, Nicoletta Crespi; Crippa, Sergio; Dal Toso, Roberto; Danieli, Bruno; Minghetti, Anacleto; Poli, Ferruccio; Pressi, Giovanna

    2011-10-01

    3,5-O-dicaffeoyl-4-O-malonilquinic acid (1) (irbic acid) has been isolated for the first time from cell cultures of Centella asiatica and till now it has never been reported to be present in the intact plant. Evidence of its structure was obtained by spectroscopic analyses (MS/NMR). Besides 1, cell cultures produce also the known 3,5-O-dicaffeoylquinic acid, chlorogenic acid, and the triferulic acid 2 (4-O-8'/4'-O-8″-didehydrotriferulic acid). Biological activities were evaluated for compound 1, which showed to have a strong radical scavenging capacity, together with a high inhibitory activity on collagenase. This suggests a possible utilization of this substance as a topical agent to reduce the skin ageing process. PMID:21635941

  18. Ent-kauren-19-oic acid derivatives from the stem bark of Croton pseudopulchellus Pax

    Langat, MK; Mulholland, DA; Crouch, NR; Tammela, P; Pohjala, L; Smith, PJ

    2012-01-01

    Two new ent-kauren-19-oic acid derivatives, ent-14S*-hydroxykaur-16-en-19-oic acid and ent-14S*,17-dihydroxykaur-15-en-19-oic acid together with eleven known compounds ent-kaur-16-en-19-oic acid, ent-kaur-16-en-19-al, ent-12β-hydroxykaur-16-en-19-oic acid, ent-12β-acetoxykaur-16-en-19-oic acid, 8R,13R-epoxylabd-14-ene, eudesm-4(15)-ene-1β,6α-diol, (-)-7-epivaleran-4-one, germacra-4(15), 5E,10(14)-trien-9β-ol, acetyl aleuritolic acid, β-amyrin, and stigmasterol were isolated from the stem bark...

  19. Synthesis and Characterization of Esters Derived from Ricinoleic Acid and Evaluation of their Low Temperature Property

    A series of ester compounds derived from ricinoleic acid to be used as bio lubricants base stock have been synthesized. The resulting products were confirmed by FTIR and NMR analyses. The synthesis was carried out in three stages: epoxidation of ricinoleic acid; synthesis of 10,12-dihydroxy-9-acyloxy stearic acid from epoxidized ricinoleic acid with various fatty acids and esterification of the acyloxy stearic acid products with octanol to yield octyl-10,12-dihydroxy-9-acyloxy stearate. The viscosities, flash points and pour points (PP) behavior of the products were measured. The resulting esters had an increased in molar weight and viscosity and decreased in pour points as compared to ricinoleic acid. (author)

  20. Microbial production of amino acids and derived chemicals: synthetic biology approaches to strain development.

    Wendisch, Volker F

    2014-12-01

    Amino acids are produced at the multi-million-ton-scale with fermentative production of l-glutamate and l-lysine alone being estimated to amount to more than five million tons in the year 2013. Metabolic engineering constantly improves productivities of amino acid producing strains, mainly Corynebacterium glutamicum and Escherichia coli strains. Classical mutagenesis and screening have been accelerated by combination with intracellular metabolite sensing. Synthetic biology approaches have allowed access to new carbon sources to realize a flexible feedstock concept. Moreover, new pathways for amino acid production as well as fermentative production of non-native compounds derived from amino acids or their metabolic precursors were developed. These include dipeptides, α,ω-diamines, α,ω-diacids, keto acids, acetylated amino acids and ω-amino acids. PMID:24922334

  1. Effect of the structure of gallic acid and its derivatives on their interaction with plant ferritin.

    Wang, Qunqun; Zhou, Kai; Ning, Yong; Zhao, Guanghua

    2016-12-15

    Gallic acid and its derivatives co-exist with protein components in foodstuffs, but there is few report on their interaction with proteins. On the other hand, plant ferritin represents not only a novel class of iron supplement, but also a new nanocarrier for encapsulation of bioactive nutrients. However, plant ferritin is easy to be degraded by pepsin in the stomach, thereby limiting its application. Herein, we investigated the interaction of gallic acid and its derivatives with recombinant soybean seed H-2 ferritin (rH-2). We found that these phenolic acids interacted with rH-2 in a structure-dependent manner; namely, gallic acid (GA), methyl gallate (MEGA) and propyl gallate (PG) having three HO groups can bind to rH-2, while their analogues with two HO groups cannot. Consequently, such binding largely inhibited ferritin degradation by pepsin. These findings advance our understanding of the relationship between the structure and function of phenolic acids. PMID:27451180

  2. Bioconversion of volatile fatty acids derived from waste activated sludge into lipids by Cryptococcus curvatus.

    Liu, Jia; Liu, Jia-Nan; Yuan, Ming; Shen, Zi-Heng; Peng, Kai-Ming; Lu, Li-Jun; Huang, Xiang-Feng

    2016-07-01

    Pure volatile fatty acid (VFA) solution derived from waste activated sludge (WAS) was used to produce microbial lipids as culture medium in this study, which aimed to realize the resource recovery of WAS and provide low-cost feedstock for biodiesel production simultaneously. Cryptococcus curvatus was selected among three oleaginous yeast to produce lipids with VFAs derived from WAS. In batch cultivation, lipid contents increased from 10.2% to 16.8% when carbon to nitrogen ratio increased from about 3.5 to 165 after removal of ammonia nitrogen by struvite precipitation. The lipid content further increased to 39.6% and the biomass increased from 1.56g/L to 4.53g/L after cultivation for five cycles using sequencing batch culture (SBC) strategy. The lipids produced from WAS-derived VFA solution contained nearly 50% of monounsaturated fatty acids, including palmitic acid, heptadecanoic acid, ginkgolic acid, stearic acid, oleic acid, and linoleic acid, which showed the adequacy of biodiesel production. PMID:27038264

  3. Photochemical synthesis and anticancer activity of barbituric acid, thiobarbituric acid, thiosemicarbazide, and isoniazid linked to 2-phenyl indole derivatives.

    Laxmi, S Vijaya; Rajitha, G; Rajitha, B; Rao, Asha Jyothi

    2016-04-01

    2-Phenyl-1H-indole-3-carbaldehyde-based barbituric acid, thiobarbituric acid, thiosemicarbazide, isoniazid, and malononitrile derivatives were synthesized under photochemical conditions. The antitumor activities of the synthesized compounds were evaluated on three different human cancer cell lines representing prostate cancer cell line DU145, Dwivedi (DWD) cancer cell lines, and breast cancer cell line MCF7. All the screened compounds possessed moderate anticancer activity, and out of all the screened compounds, 5-{1[2-(4-chloro-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2b) and 5-{1[2-(4-methoxy-phenyl)2-oxo-ethyl]-2-phenyl-1H-indole-3-ylmethylene}-2-thioxo-dihydro-pyrimidine-4,6-dione (2d) exhibited marked antitumor activity against used cell lines. Additionally, barbituric acid derivatives were selective to inhibit cell line DWD and breast cancer cell lines. PMID:27118996

  4. Peptide receptor radionuclide therapy (PRRT) of neuroendocrine tumors: First comparative results using the somatostatin analogues Lu-177 DOTA-NOC and Lu-177 DOTA-TATE

    Peptide receptor radionuclide therapy (PRRT) is used in our department since 5 years (approx. 400 applications) for the treatment of patients with metastatic neuroendocrine tumors. Of all known peptides, the somatostatin analogue DOTA-NOC shows in vitro the highest affinity to somatostatin receptors (sstr) 3 and 5 and a very high affinity to sstr 2. We studied the in vivo behaviour of the two peptides DOTA-NOC and DOTA-TATE (highest affinity to sstr 2) by the use of different parameters like tumor and organ uptake, effective half-lifes (kinetics) and mean absorbed organ and tumor doses. We studied 27 patients with metastatic neuroendocrine tumors with high somatostatin expression, as verified prior to treatment by Ga-68 DOTA-NOC receptor PET/CT or somatostatin receptor scintigraphy (Tc-99m EDDA-Hynic TOC or In-111 OctreoScan, planar and SPECT). 22 patients (8M and 14F; aged 619 years) were treated with 2500 6790 MBq Lu-177 DOTA-TATE. Another 5 patients (1M and 4F, aged 6310 years) were treated with 4000 7400 MBq Lu-177 DOTA-NOC. Labelling efficiency and radiochemical purity using Lutetium-177 chloride (obtained from PerkinElmer Life Sciences, USA) were constantly over 99.5%. Whole-body scans (anterior/posterior) were performed at 0.5h, 3h, 24h, 48h, 72h and 96h p.i. ROIs were drawn over the whole-body, organs, and different metastases (mainly in the liver). Blood samples were obtained in 12 patients after therapy with Lu-177 DOTA-TATE over 5 days for calculating the kinetics in blood. The ROI results were used to determine the uptake and effective half-life in different organs (kidney, spleen, liver, bone etc.) and the tumor residence times. By means of geometric mean, and after background correction, the ROI results were also used to calculate the estimated absorbed organ and tumor doses using the OLINDA software. Compared to Lu-177 DOTA-TATE (=100%), the uptake of Lu-177 DOTA-NOC was higher for the whole-body (45%) and for normal tissues (28%), and also in the

  5. Synthesis and biological activity of 125I/127I-phenylboronic acid derivatives

    Three iodinated phenylboronic acids have been synthesized: 4-iodophenylboronic acid (2a), 3-(4-iodobenzenesulfonamido) phenylboronic acid (5a) and 3-(5-dimethylamino-6-iodo-1-naphthalene-sulfonamido)-phenylboronic acid (6a). The corresponding no-carrier-added 125I derivatives 2b, 5b and 6b have been prepared in good yield by selective displacement of the tributylstannyl group. Compound 6b was concentrated in vitro preferentially in HT-29 human colon carcinoma cells compared to V79 Chinese hamster lung fibroblasts and showed selective retention in PaCa-2 human pancreatic cancer cells grown as solid tumor xenografts in the nude mouse. (author)

  6. Spectrophotometric study into complexing of vanadium(3) with salicylic acid derivatives

    Complexing of vanadium (3) with 5 amino-salicylic acid and amide of salicylhydroxamic acid has been studied. It has been shown that in acidic medium V3+ forms yellow complexes of the composition 1:1 with instability constants 2.2x10-19, 7.8x10-11, and 2.2x10-12, respectively. Complexes of V3+ with derivatives of salicylic acid can be used for determining V(3) content in the presence of V(4)

  7. Synthesis of derivatives of tetronic acid and pulvinic acid. Total synthesis of norbadione A

    When vegetables like mushrooms are contaminated by radioactive caesium 137, this radioactive caesium is associated to norbadione A, a natural pigment present in two mushroom species and which can be used as a caesium decorporation agent or maybe as protection agent against ionizing radiations. Within this perspective, this research report describes the biosynthesis and the structure and properties of the norbadione A and of pulvinic acids (physicochemical properties, anti-oxidizing properties). Then, it presents the various tetronic acids (3-acyl-, 3-alkyl-, 3-alkoxy-, 3-aryl-tetronic acids and non 3-substituted tetronic acids), their synthesis path as they are described in the literature, and presents a new synthesis approach using a tandem reaction (with different esters or hydroxy esters) and the synthesis of tetronic acids. The author also proposes a new synthesis way for methyl pulvinates, and finally reports the work on the development of a total synthesis of the norbadione A

  8. Docosapentaenoic acid derived metabolites and mediators - The new world of lipid mediator medicine in a nutshell.

    Weylandt, Karsten-H

    2016-08-15

    Recent years have seen the description and elucidation of a new class of anti-inflammatory and pro-resolving lipid mediators. The arachidonic acid (AA)-derived compounds in this class are called lipoxins and have been described in great detail since their discovery thirty years ago. The new players are mediators derived from fish oil omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), called resolvins, protectins and maresins. Taken together, these mediators are also called specialized pro-resolution mediators (SPMs). As compared to the AA/EPA/DHA-derived compounds, research regarding mediators formed from the n-3 and n-6 docosapentaenoic acids (DPAn-3 and DPAn-6) is sparse. However, mono- di- and trihydroxy derivates of the DPAs have anti-inflammatory properties as well, even though mechanisms of their anti-inflammatory action have not been fully elucidated. This review aims to summarize current knowledge regarding the DPA-derived SPMs and their actions. PMID:26546723

  9. Site-specific DOTA/europium-labeling of recombinant human relaxin-3 for receptor-ligand interaction studies.

    Zhang, Wei-Jie; Luo, Xiao; Liu, Ya-Li; Shao, Xiao-Xia; Wade, John D; Bathgate, Ross A D; Guo, Zhan-Yun

    2012-08-01

    Relaxin-3 (also known as INSL7) is a recently identified neuropeptide belonging to the insulin/relaxin superfamily. It has putative roles in the regulation of stress responses, food intake, and reproduction by activation of its cognate G-protein-coupled receptor RXFP3. It also binds and activates the relaxin family peptide receptors RXFP1 and RXFP4 in vitro. To obtain a europium-labeled relaxin-3 as tracer for studying the interaction of these receptors with various ligands, in the present work we propose a novel site-specific labeling strategy for the recombinant human relaxin-3 that has been previously prepared in our laboratory. First, the N-terminal 6 × His-tag of the single-chain relaxin-3 precursor was removed by Aeromonas aminopeptidase and all of the primary amines of the resultant peptide were reversibly blocked by citroconic anhydride. Second, the A-chain N-terminus of the blocked peptide was released by endoproteinase Asp-N cleavage that removed the linker peptide between the B- and A-chains. Third, an alkyne moiety was introduced to the newly released A-chain N-terminus by reaction with the highly active primary amine-specific N-hydroxysuccinimide ester. Fourth, after removal of the reversible blockage under mild acidic condition, europium-loaded DOTA with an azide moiety was introduced to the two-chain relaxin-3 carrying the alkyne moiety through click chemistry. Using this site-specific labeling strategy, homogeneous monoeuropium-labeled human relaxin-3 could be obtained with good overall yield. In contrast, conventional random labeling resulted in a complex mixture that was poorly resolved because human relaxin-3 has four primary amine moieties that all react with the modification reagent. Both saturation and competition binding assays demonstrated that the DOTA/Eu(3+)-labeled relaxin-3 retained high binding affinity for human RXFP3, RXFP4, and RXFP1 and was therefore a suitable non-radioactive and stable tracer to study the interaction of various

  10. Structure–anticancer activity relationships among 4-azolidinone-3-carboxylic acids derivatives

    Lesyk R. B.

    2010-04-01

    Full Text Available The aim of present research was investigation of anticancer activity of 4-azolidinone-3-carboxylic acids derivatives, and studies of structure–activity relationships (SAR aspects. Methods. Organic synthesis; spectral methods; anticancer screening was performed according to the US NCI protocol (Developmental Therapeutic Program. Results. The data of new 4-thiazolidinone-3-alkanecarboxylic acids derivatives in vitro anticancer activity were described. The most active compounds which belong to 5-arylidene-2,4- thia(imidazolidinone-3-alkanecarboxylic acids; 5-aryl(heterylidenerhodanine-3-succinic acids derivatives were selected. Determination of some SAR aspects which allowed to determine directions in lead- compounds structure optimization, as well as desirable molecular fragments for design of potential anticancer agents based on 4-azolidinone scaffold were performed. 5-Arylidenehydantoin-3-acetic acids amides were identified as a new class of significant selective antileukemic agents. Possible pharmacophore scaffold of 5-ylidenerhodanine-3-succinic acids derivatives was suggested. Conclusions. The series of active compounds with high anticancer activity and/or selectivity levels were selected. Some SAR aspects were determined and structure design directions were proposed.

  11. In vivo evaluation of a lead-labeled monoclonal antibody using the DOTA ligand

    The aim of this study was to assess the utility of a radioimmunoconjugate containing a lead radionuclide for therapy and scintigraphy applications. The radioimmunoconjugate evaluated consisted of a bifunctional DOTA ligand and monoclonal antibody (MAb) B72.3 using athymic mice bearing LS-174T tumors, human colon carcinoma xenografts. In the studies reported here, the lead-203-DOTA complex itself was first demonstrated to have in vivo stability. MAb B72.3 was then conjugated with the DOTA ligand and labeled with 203Pb, and the immunoreactivity of B72.3 was maintained. The localization of the radioimmunoconjugate to tumor tissue and other select organs paralleled that of DOTA-125I-B72.3, suggesting a similar metabolic pattern of the two radioimmunoconjugates. Thus, the DOTA-metal complex does not alter the behavior of the radioimmunoconjugate. Tumor localization of the 203Pb-DOTA-B72.3 conjugate was demonstrated with biodistribution studies as well as immunoscintigraphy studies. Such data highlight the stability of a lead radionuclide in the DOTA ligand. The suitability of this chelation chemistry for labeling radioimmunoconjugates with a lead radionuclide now makes its application in nuclear medicine a feasible proposition. (orig.)

  12. New Biocompatible Polyesters Derived from α-Amino Acids: Hydrolytic Degradation Behavior

    Jeoshua Katzhendler

    2010-10-01

    Full Text Available New polymers were synthesized from α-hydroxy acids derived from the natural amino acids Ile, Leu, Phe, and Val, combined with lactic acid, glycolic acid and 6-hydroxyhexanoic acid by direct condensation. The toxicity was determined and the degradation process of these polyesters was investigated under physiological conditions by analyzing the composition of the degraded polymers and the oligomers cleaved in the buffer medium. The polymers were found to be non toxic to two cell lines. Polymers displayed a biphasic degradation behavior. In most cases, a linear relationship was found between the weight loss constant and the hydrophobicity of the polymers, Log P. Regarding the second stage of weight loss, it is apparent that polymers derived from α-hydroxy(Lisoleucine ((LHOIle and α-hydroxy(LValine ((LHOVal degraded much faster than those derived from α-hydroxy(Lleucine ((LHOLeu and α-hydroxy(Lphenylalanine ((LHOPhe, probably due to different spatial orientation of the side chains. Copolymers of 6-hydroxyhexanoic acid displayed slow degradation rates as expected, whereas the degradation profile of copolymers of lactic acid was similar to the other homopolymers. These new polyesters may serve as potential biocompatible materials for medical applications.

  13. Neuraminidase inhibition of Dietary chlorogenic acids and derivatives - potential antivirals from dietary sources.

    Gamaleldin Elsadig Karar, Mohamed; Matei, Marius-Febi; Jaiswal, Rakesh; Illenberger, Susanne; Kuhnert, Nikolai

    2016-04-20

    Plants rich in chlorogenic acids (CGAs), caffeic acids and their derivatives have been found to exert antiviral effects against influenza virus neuroaminidase. In this study several dietary naturally occurring chlorogenic acids, phenolic acids and derivatives were screened for their inhibitory activity against neuroaminidases (NAs) from C. perfringens, H5N1 and recombinant H5N1 (N-His)-Tag using a fluorometric assay. There was no significant difference in inhibition between the different NA enzymes. The enzyme inhibition results indicated that chlorogenic acids and selected derivatives, exhibited high activities against NAs. It seems that the catechol group from caffeic acid was important for the activity. Dietary CGA therefore show promise as potential antiviral agents. However, caffeoyl quinic acids show low bioavailibility and are intensly metabolized by the gut micro flora, only low nM concentrations are observed in plasma and urine, therefore a systemic antiviral effect of these compounds is unlikely. Nevertheless, gut floral metabolites with a catechol moiety or structurally related dietary phenolics with a catechol moiety might serve as interesting compounds for future investigations. PMID:27010419

  14. Labelling of the peptide Dota-Octreotate with Lutetium 177

    In this work is described the optimization of the reaction conditions to obtain the complex 177 Lu-Dota-TATE with a radiochemical purity > 95%, even so the studies of stability In vitro to the dilution in saline solution, stability in human serum and challenge to the cystein. The biodistribution studies are presented in mice Balb-C and the tests of biological recognition using one lines cellular of pancreatic adenoma (AR42-J). The obtained results show a high stability of the radio complex in vitro, since it doesn't suffer trans chelation from the Lutetium-177 to plasmatic proteins. The biodistribution tests in mice Balb-C demonstrated an appropriate lipophilly of the complex to be excreted in more proportion by the kidneys without significant accumulation in healthy tissues. It is necessary to mention that the drop activity specifies (3.54 μg / 37 MBq) obtained in the irradiation of 176 Lu2O3 it allowed to verify the union of the 177Lu-Dota-Tate to membrane receivers but without being able to obtain the saturation curves and competition required to characterize quantitatively the biological recognition. (Author)

  15. The synthesis of barbituric acid and some of its derivatives isotopically labelled with 15N

    Full text: Barbituric acid is the parent compound of a large class of barbiturates that have central nervous system depressant properties, although barbituric acid itself is not pharmacologically active. In recent years, barbituric acid derivatives have been studied as antitumor, anticancer and anti-osteoporosis agents. The aim of this paper is to present the synthesis of barbituric acid-15N, 5,5-diethylbarbituric acid-15N (Veronal-15N) and 5-ethyl-5-phenylbarbituric acid- 15N (Phenobarbitone-15N) . As isotopically labelled material we used urea-15N2, 99 at.% 15N produced at National Institute for Research and Development of Isotopic and Molecular Technologies, Cluj-Napoca, Romania. All compounds were fully characterized by Mass Spectrometry analyses, by FT-IR Spectroscopy and RX Diffraction, and the isotopic label was determined by MS on the molecular compounds. (author)

  16. Antitrypanosomal Activity of Novel Benzaldehyde-Thiosemicarbazone Derivatives from Kaurenoic Acid

    Cecília M. A. de Oliveira

    2011-01-01

    Full Text Available A series of new thiosemicarbazones derived from natural diterpene kaurenoic acid were synthesized and tested against the epimastigote forms of Trypanosoma cruzi to evaluate their antitrypanosomal potential. Seven of the synthesized thiosemicarbazones were more active than kaurenoic acid with IC50 values between 2-24.0 mM. The o-nitro-benzaldehyde-thiosemicarbazone derivative was the most active compound with IC50 of 2.0 mM. The results show that the structural modifications accomplished enhanced the antitrypanosomal activity of these compounds. Besides, the thiocyanate, thiosemicarbazide and the p- methyl, p-methoxy, p-dimethylamine, m-nitro and o-chlorobenzaldehyde-thiosemicarbazone derivatives displayed lower toxicity for LLMCK2 cells than kaurenoic acid, exhibing an IC50 of 59.5 mM.

  17. Crystal Structure and Properties of the Carboxylic Acid Derivatives of Schizonpeta mulifida (L.) Briq.

    LIU,Ju-Tao; YU,Ji-Cheng; JIANG,Hui-Ming; ZHANG,Li-Ying; ZHAO,Xiao-Jing; FAN,Sheng-Di

    2008-01-01

    The chemical constituents of the carboxylic acid derivatives from the ear of Schizonepeta were investigated,1H and 13C NMR chemical shifts of the carboxylic acid derivatives were accurately assigned.Two carboxylic acid derivative constituents were separated by a silica gel column.The structures were elucidated by the physical and chemical properties,IR,1H NMR,13C NMR,MALDI-TDF-MS and X-ray single crystal diffractometry.They were identified as 3-imino-N-(a-imidoethylamino)butyrolactam and neononane tetracid,respectively.The antitumoral activity on liver tumor ceils SMMC-7721 was determined in vitro.The experimental results showed that the former was better than the latter,and with increasing the concentration of the former the inhibitory activity was increased.

  18. Lanthanum(III) and praseodymium(III) derivatives with dithiocarbamates derived from alpha-amino acids.

    Rai, Anita; Sengupta, Soumitra K; Pandey, Om P

    2006-06-01

    Lanthanum(III) and praseodymium(III) complexes with dithiocarbamates have been synthesized by the reactions of lanthanum(III) and praseodymium(III) chloride with barium dithiocarbamate and complexes of type [LnCl(L)H2O]n have been obtained (where Ln=La(III) or Pr(III); L=barium salt of dithiocarbamate derived from glycine, L-leucine, L-valine, DL-alanine). The complexes have been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H NMR spectral studies. The presence of coordinated water molecule is inferred from thermogravimetric analysis which indicates the loss of one water molecule at 150-170 degrees C. The oscillator strength, Judd-Ofelt intensity parameter, stimulated emission cross-section, etc. have been obtained for different transitions of Pr3+. PMID:16330242

  19. Lanthanum(III) and praseodymium(III) derivatives with dithiocarbamates derived from α-amino acids

    Rai, Anita; Sengupta, Soumitra K.; Pandey, Om P.

    2006-06-01

    Lanthanum(III) and praseodymium(III) complexes with dithiocarbamates have been synthesized by the reactions of lanthanum(III) and praseodymium(III) chloride with barium dithiocarbamate and complexes of type [LnCl(L)H 2O] n have been obtained (where Ln = La(III) or Pr(III); L = barium salt of dithiocarbamate derived from glycine, L-leucine, L-valine, DL-alanine). The complexes have been characterized by elemental analysis, molar conductance, electronic absorption and fluorescence, infrared, far infrared, 1H NMR spectral studies. The presence of coordinated water molecule is inferred from thermogravimetric analysis which indicates the loss of one water molecule at 150-170 °C. The oscillator strength, Judd-Ofelt intensity parameter, stimulated emission cross-section, etc. have been obtained for different transitions of Pr 3+.

  20. A Direct, Biomass-Based Synthesis of Benzoic Acid: Formic Acid-Mediated Deoxygenation of the Glucose-Derived Materials Quinic Acid and Shikimic Acid

    Arceo, Elena; Ellman, Jonathan; Bergman, Robert

    2010-05-03

    An alternative biomass-based route to benzoic acid from the renewable starting materials quinic acid and shikimic acid is described. Benzoic acid is obtained selectively using a highly efficient, one-step formic acid-mediated deoxygenation method.

  1. Technological and economic potential of poly(lactic acid) and lactic acid derivatives

    Datta, R.; Tsai, S.P.; Bonsignore, P.; Moon, S.H.; Frank, J.R.

    1993-10-01

    Lactic acid has been an intermediate-volume specialty chemical (world production {approximately}40,000 tons/yr) used in a wide range of food processing and industrial applications. lactic acid h,as the potential of becoming a very large volume, commodity-chemical intermediate produced from renewable carbohydrates for use as feedstocks for biodegradable polymers, oxygenated chemicals, plant growth regulators, environmentally friendly ``green`` solvents, and specially chemical intermediates. In the past, efficient and economical technologies for the recovery and purification of lactic acid from crude fermentation broths and the conversion of tactic acid to the chemical or polymer intermediates had been the key technology impediments and main process cost centers. The development and deployment of novel separations technologies, such as electrodialysis (ED) with bipolar membranes, extractive distillations integrated with fermentation, and chemical conversion, can enable low-cost production with continuous processes in large-scale operations. The use of bipolar ED can virtually eliminate the salt or gypsum waste produced in the current lactic acid processes. In this paper, the recent technical advances in tactic and polylactic acid processes are discussed. The economic potential and manufacturing cost estimates of several products and process options are presented. The technical accomplishments at Argonne National Laboratory (ANL) and the future directions of this program at ANL are discussed.

  2. In vitro Evaluation of a Bombesin Antagonistic Analogue Conjugated with DOTA-Ala(SO{sub 3}H)-Aminooctanoyl for Targeting of the Gastrin-releasing Peptide Receptor

    Lim, Jae Cheong; Cho, Eun Ha; Kim, Jin Joo; Lee, So Young; Choi, Sang Mu [Korea Atomic Energy Research Institute, Daejeon (Korea, Republic of)

    2014-05-15

    As Bombesin (BBS) binds with high affinity to GRPR, BBS derivatives have been labeled with various radionuclides such as {sup 99}mTc, {sup 111}In, {sup 90}Y, {sup 64}Cu, {sup 177}Lu, {sup 68}Ga, or {sup 18}F and have proved to be successful candidates for peptide receptor radiotherapy (PRRT). In this study, we employed Ala(SO{sub 3}H)-Aminooctanoyl as a linker of BBS antagonistic peptide sequence, Gln-Trp-Ala-Val-N methyl Gly-His-Statine-Leu-NH{sub 2}, with DOTA to prepare radiolabeled candidates for GRPR targeting. A DOTA-conjugated BBS antagonistic analogue was synthesized and radiolabeled with {sup 177}Lu, and in vitro characteristics on GRPR-overexpressing human prostate tumor cells were evaluated. In conclusion, a novel BBS antagonistic analogue, {sup 177}Lu-DOTA-sBBNA, is a promising candidate for the targeting of GRPR-over-expressing tumors. Further investigations to evaluate its in vivo characteristics and therapeutic efficacy are needed.

  3. 177Lu-DOTA-HH1, a novel anti-CD37 radio-immunoconjugate: a study of toxicity in nude mice.

    Ada H V Repetto-Llamazares

    Full Text Available CD37 is an internalizing B-cell antigen expressed on Non-Hodgkin lymphoma (NHL and chronic lymphocytic leukemia cells (CLL. The anti-CD37 monoclonal antibody HH1 was conjugated to the bifunctional chelator p-SCN-Bn-DOTA and labelled with the beta-particle emitting radionuclide 177Lu creating the radio-immunoconjugate (RIC 177Lu-DOTA-HH1 (177Lu-HH1, trade name Betalutin. The present toxicity study was performed prior to initiation of clinical studies with 177Lu-HH1.Nude mice with or without tumor xenografts were treated with 50 to 1000 MBq/kg 177Lu- HH1 and followed for clinical signs of toxicity up to ten months. Acute, life threatening bone marrow toxicity was observed in animals receiving 800 and 1000 MBq/kg 177Lu-HH1. Significant changes in serum concentrations of liver enzymes were evident for treatment with 1000 MBq/kg 177Lu-HH1. Lymphoid depletion, liver necrosis and atrophy, and interstitial cell hyperplasia of the ovaries were also observed for mice in this dose group.177Lu-DOTA-HH1 was well tolerated at dosages about 10 times above those considered relevant for radioimmunotherapy in patients with B-cell derived malignancies.The toxicity profile was as expected for RICs. Our experimental results have paved the way for clinical evaluation of 177Lu-HH1 in NHL patients.

  4. Design and synthesis of novel Y-shaped barbituric acid derivatives as PPARγ activators.

    Dixit, Vaibhav A; Rathi, Prakash Chandra; Bhagat, Shweta; Gohlke, Holger; Petersen, Rasmus K; Kristiansen, Karsten; Chakraborti, Asit K; Bharatam, Prasad V

    2016-01-27

    Novel Y-shaped barbituric acid (BA) derivatives have been designed using rational methods including molecular docking. Fourteen novel compounds were synthesized using hydroxyl group protection-deprotection strategies for PPARγ activation. Competitive binding analysis of the synthesized molecules using time-resolved fluorescence resonance energy transfer (FRET) method was carried out, and the IC50 values were determined. The symmetrically substituted derivatives have shown greater binding affinity than unsymmetrically substituted derivatives. Nitrobenzyl and cyanophenyl substituted derivatives have shown reasonable binding affinities (10.1 and 6.5 μM, respectively), while mono and diacetate derivatives were found inactive. Molecular dynamics simulations show that the designed compounds have interaction profiles similar to partial agonists. The most significant finding of our study is that BA derivatives with symmetrically substituted weakly polar side chains result in the desired moderate level of PPARγ binding affinities. PMID:26708109

  5. Novel self-associative and multiphase nanostructured soft carriers based on amphiphilic hyaluronic acid derivatives

    Eenschooten, Corinne; Vaccaro, Andrea; Delie, Florence;

    2012-01-01

    The purpose of the present study was to investigate the physicochemical properties in aqueous media of amphiphilic hyaluronic acid (HA) derivatives obtained by reaction of HA’s hydroxyl groups with octenyl succinic anhydride (OSA). The self-associative properties of the resulting octenyl succinic...... anhydridemodified hyaluronic acid (OSA-HA) derivatives were studied by fluorescence spectroscopy using Nile Red as fluorophore. The morphology, size and surface charge of the OSA-HA assemblies were determined by transmission electron microscopy, dynamic light scattering and by measuring their electrophoretic...

  6. Effect of vanillin and its acid and alcohol derivatives on the diphenolase activity of mushroom tyrosinase

    Masoomeh Bagheri-Kalmarzi; Sajedi, Reza H.; Elham Asadollahi; Nosrat O. Mahmoodi; Reza Haji-Hosseini

    2012-01-01

    For the first time in the present study the effects of vanillin, vanillyl alcohol, vanillic acid, as well as the newly synthesized vanillin derivative, bis-vanillin, were investigated on the oxidation of dopamine hydrochloride by mushroom tyrosinase. Among them, vanillin and bis-vanillin act as activators, while vanillyl alcohol and vanillic acid exhibited inhibitory effects, the IC50 values being estimated 1.5 and 1.0 mM, respectively. These compounds were mixed inhibitors. The presence of a...

  7. Cytotoxicity of Coprinopsis atramentaria extract, organic acids and their synthesized methylated and glucuronate derivatives

    Heleno, Sandrina A.; Isabel C. F. R. Ferreira; Calhelha, Ricardo C.; Esteves, Ana P.; Martins, Anabela; Queiroz, Maria João R. P.

    2014-01-01

    Coprinopsis atramentaria is a wild edible mushroom whose methanolic extract revealed a marked antioxidant activity; p-hydroxybenzoic (HA), p-coumaric (CoA) and cinnamic (CA) acids were identified in the extract. In the present work, the cytotoxicity of C. atramentaria extract, previously identified organic acids and their synthesized derivatives (methylated compounds and protected glucuronides) was evaluated. Among all the tested cell lines (MCF-7—breast adenocarcinoma, NCI-H460—non-small cel...

  8. Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives

    Antimo Gioiello; Antonio Macchiarulo; Roberto Pellicciari; Roberto Nuti; Roccaldo Sardella; Benedetto Natalini; Paola Sabbatini; Paolo Filipponi

    2013-01-01

    Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and metabolic diseases have extended the scope of this class of steroids for in vivo investigations. In this framework, the design and synthesis of novel biliary derivatives able to modulate a specific...

  9. Use of Hydrazone Derivates as Inhibitors for the Corrosion of Nickel in Hydrochloric Acid Solution

    A.S. Fouda, H. A. Mostafa, S. E. Ghazy and S. A. El- Farah

    2007-01-01

    The influence of hydrazone derivatives on the corrosion of nickel in 2 mol L-1 hydrochloric acid solution has been studied using weight loss and galvanostatic polarization techniques. In general, at constant acid concentration, the inhibition efficiency increases with increasing the inhibitor concentration and decreases with increasing temperature. Polarization studies indicate that the compounds act as mixed- type inhibitors. The addition of iodide ions enhances the inhibition efficiency to ...

  10. Phenolic Acids, Phenolic Aldehydes and Furanic Derivatives in Oak Chips: American vs. French Oaks

    Cabrita, M.J.; Barrocas Dias, C.; Costa Freitas, A.M.

    2011-01-01

    Phenolic acids (gallic, vanillic, syringic and ellagic acids), phenolic aldehydes (vanillin, syringaldehyde, coniferaldehyde and sinapaldehyde) and furanic derivatives (furfural, 5-methylfurfural and 5-hydroxymethylfurfural) were quantified in commercial American and French oak chips. Chips with different sizes and toast degrees were used. Compounds were extracted directly from the wood samples in order to determine possible differences among woods as well as toast degree. Likewise, the compo...

  11. Recent developments in altering the fatty acid composition of ruminant-derived foods

    Shingfield, Kevin; Bonnet, Muriel; Scollan, Nigel

    2013-01-01

    There is increasing evidence to indicate that nutrition is an important factor involved in the onset and development of several chronic human diseases including cancer, cardiovascular disease (CVD), type II diabetes and obesity. Clinical studies implicate excessive consumption of medium-chain saturated fatty acids (SFA) and trans-fatty acids (TFA) as risk factors for CVD, and in the aetiology of other chronic conditions. Ruminant-derived foods are significant sources of medium-chain SFA and T...

  12. Labelling of the peptide Dota-Octreotate with Lutetium 177; Marcado del peptido Dota-Octreotate con Lutecio 177

    Hernandez B, C.A

    2004-07-01

    In this work is described the optimization of the reaction conditions to obtain the complex {sup 177} Lu-Dota-TATE with a radiochemical purity > 95%, even so the studies of stability In vitro to the dilution in saline solution, stability in human serum and challenge to the cystein. The biodistribution studies are presented in mice Balb-C and the tests of biological recognition using one lines cellular of pancreatic adenoma (AR42-J). The obtained results show a high stability of the radio complex in vitro, since it doesn't suffer trans chelation from the Lutetium-177 to plasmatic proteins. The biodistribution tests in mice Balb-C demonstrated an appropriate lipophilly of the complex to be excreted in more proportion by the kidneys without significant accumulation in healthy tissues. It is necessary to mention that the drop activity specifies (3.54 {mu}g / 37 MBq) obtained in the irradiation of {sup 176} Lu{sub 2}O{sub 3} it allowed to verify the union of the {sup 177}Lu-Dota-Tate to membrane receivers but without being able to obtain the saturation curves and competition required to characterize quantitatively the biological recognition. (Author)

  13. Bioactivity and Chemical Synthesis of Caffeic Acid Phenethyl Ester and Its Derivatives

    Pengxuan Zhang

    2014-10-01

    Full Text Available Caffeic acid phenethyl ester (CAPE, as one of the main active ingredients of the natural product propolis, shows the unique biological activities such as anti-tumor, anti-oxidation, anti-inflammatory, immune regulation, and so on. These have attracted the attention of many researchers to explore the compound with potent biological activities. This review aims to summarize its bioactivities, synthetic methods and derivatives, which will be helpful for further study and development of CAPE and its derivatives.

  14. The Effect of the Serum Amino Acid Levels Thiosemicarbazone Derivatives and its Metal Complexes on Rats

    Karatepe, Mustafa; Kaman, Dilara

    2013-01-01

    Advers biological activities of Thiosemicarbazone (TSC) and Schiff base (SB) derivatives have been widely studied in rats and in other animal species using different doses, times and routes of administration. To date, no attempt has been made to study alterations occurring in the amino acid profile in the effects of the thiosemicarbazone derivative and its metal complexes on the rats. At this study, the rats were injected subcutaneously with a new thiosemicarbazone and its LH-Zn and LH-Cu com...

  15. Cyclic derivatives of D-glucose and tartaric acid as building blocks for renewable polyesters

    Japu, Cristina

    2014-01-01

    Three series of aromatic copolyesters derived from poly(ethylene terephthalate) (PET), poly(butylene terephthalate) (PBT) and poly(hexamethylene terephthalate) (PHT) have been synthesized by melt polycondensation in which the terephthalate and oxyalkylene units have been partially or totally replaced by monocyclic and bicyclic diacids and diols obtained by derivatization of renewable monomers such as tartaric acid and D-glucose respectively. Another series of aliphatic copolyesters derived f...

  16. Synthesis of 5-,6-, and 7-membered heterocycles from barbituric acid derivatives

    Guyader, David

    2011-01-01

    SUMMARY A new procedure has been developed for the synthesis of barbituric acid derivatives. The reactions were performed under solvent free conditions without any catalyst. Employing this synthetic route, a large number of chalconoids and 5-,6-, and 7-membered heterocycles have been successfully synthesized in a very short time. The chalconoids have been synthesized from a barbituric derivative and substituted benzaldehydes. The effect of different substituents on the yield of the re...

  17. Peptaibols, Tetramic Acid Derivatives, Isocoumarins and Sesquiterpenes from a Bionectria sp. (MSX 47401)

    Figueroa, Mario; Raja, Huzefa; Falkinham, Joseph O.; Adcock, Audrey F.; Kroll, David J; Wani, Mansukh C.; Pearce, Cedric J.; Oberlies, Nicholas H.

    2013-01-01

    An extract of the filamentous fungus Bionectria sp. (MSX 47401) showed both promising cytotoxic activity (>90% inhibition of H460 cell growth at 20 μg/mL) and antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA). A bioactivity-directed fractionation study yielded one new peptaibol (1) and one new tetramic acid derivative (2), and the fungus biosynthesized diverse secondary metabolites with mannose derived units. Five known compounds were also isolated: clonostachi...

  18. Preparation and adsorption behavior for metal ions and humic acid of chitosan derivatives crosslinked by irradiation

    2007-01-01

    This article deals with the determination of the adsorption properties of metal ions and humic acid in water on crosslinked chitosan derivatives (carboxymethylchitosan) which were formed using the irradiation technique without any additives. The solubility test of these crosslinked materials were investigated in acidic, alkaline media,distilled water, and certain organic solvents. Scanning electron microscopic (SEM) images showed that the crosslinked chitosan derivatives possessed a porous morphological structure. Charged characteristic analyses demonstrated typically pH-dependent properties of the crosslinked materials. The adsorption studies were carried out by the batch method at room temperature. Adsorption of heavy metal ions (such as Cu2+, Cd2+) and humic acid onto crosslinked samples was found to be strongly pH-dependent. Adsorption kinetic studies indicated the rapid removal of metal ions, and humic acid from the aqueous solutions. Moreover, isothermal adsorption data revealed that Cu2+, Cd2+,and humic acid were removed by these crosslinked materials with high efficiency. Adsorption isothermal data were interpreted well by the Langmuir equation. These crosslinked carboxymethylated chitosan derivatives indicate favorable adsorption of metal ions and humic acid.

  19. Implications for eicosapentaenoic acid- and docosahexaenoic acid-derived resolvins as therapeutics for arthritis.

    Souza, Patricia R; Norling, Lucy V

    2016-08-15

    Omega-3 polyunsaturated fatty acids are essential for health and are known to possess anti-inflammatory properties, improving cardiovascular health as well as benefiting inflammatory diseases. Indeed, dietary supplementation with omega-3 polyunsaturated fatty acids has proved efficacious in reducing joint pain, morning stiffness and nonsteroidal anti-inflammatory drugs usage in rheumatoid arthritis patients. However, the mechanisms by which omega-3 polyunsaturated fatty acids exert their beneficial effects have not been fully explored. Seminal discoveries by Serhan and colleagues have unveiled a novel class of bioactive lipid mediators that are enzymatically biosynthesized in vivo from omega-3 eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), termed resolvins, protectins and maresins. These bioactive pro-resolving lipid mediators provide further rationale for the beneficial effects of fish-oil enriched diets. These endogenous lipid mediators are spatiotemporally biosynthesized to actively regulate resolution by acting on specific G protein-coupled receptors (GPCRs) to initiate anti-inflammatory and pro-resolving signals that terminate inflammation. In this review, we will discuss the mechanism of actions of these molecules, including their analgesic and bone-sparing properties making them ideal therapeutic agonists for the treatment of inflammatory diseases such as rheumatoid arthritis. PMID:26165764

  20. Bile acid derivatives as ligands of the farnesoid x receptor: molecular determinants for bile acid binding and receptor modulation.

    Gioiello, Antimo; Cerra, Bruno; Mostarda, Serena; Guercini, Chiara; Pellicciari, Roberto; Macchiarulo, Antonio

    2014-01-01

    Bile acids are a peculiar class of steroidal compounds that never cease to amaze. From being simple detergents with a primary role in aiding the absorption of fats and fat-soluble vitamins, bile acids are now widely considered as crucial hormones endowed with genomic and non-genomic functions that are mediated by their interaction with several proteins including the nuclear receptor Farnesoid X Receptor (FXR). Taking advantages of the peculiar properties of bile acids in interacting with the FXR receptor, several biliary derivatives have been synthesized and tested as FXR ligands. The availability of these compounds has contributed to characterize the receptor from a structural, patho-physiological and therapeutic standpoint. Among these, obeticholic acid is a first-in-class FXR agonist that is demonstrating hepatoprotective effects upon FXR activation in patients with liver diseases such as primary biliary cirrhosis and nonalcoholic steatohepatitis. This review provides an historical overview of the rationale behind the discovery of obeticholic acid and chemical tools generated to depict the molecular features and bio-pharmacological relevance of the FXR receptor, as well as to summarize structure-activity relationships of bile acid-based FXR ligands so far reported. PMID:25388535

  1. MR Diagnosis of a Pulmonary Embolism: Comparison of P792 and Gd-DOTA for First-Pass Perfusion MRI and Contrast-Enhanced 3D MRA in a Rabbit Model

    Keilholz, Shella D. [Emory University and Georgia Institute of Technology, Atlanta (United States); Bozlar, Ugur; Fujiwara, Naomi; Mata, Jaime F.; Berr, Stuart S.; Hagspiel, Klaus D. [Gulhane Military Medical Academy, Ankara (Turkmenistan); Corot, Claire [Guerbet Research, Aulnay-sous-Bois (France)

    2009-10-15

    To compare P792 (gadomelitol, a rapid clearance blood pool MR contrast agent) with gadolinium-tetraazacyclododecanetetraacetic acid (Gd- DOTA), a standard extracellular agent, for their suitability to diagnose a pulmonary embolism (PE) during a first-pass perfusion MRI and 3D contrastenhanced (CE) MR angiography (MRA). A perfusion MRI or CE-MRA was performed in a rabbit PE model following the intravenous injection of a single dose of contrast agent. The time course of the pulmonary vascular and parenchymal enhancement was assessed by measuring the signal in the aorta, pulmonary artery, and lung parenchyma as a function of time to determine whether there is a significant difference between the techniques. CE-MRA studies were evaluated by their ability to depict the pulmonary vasculature and following defects between 3 seconds and 15 minutes after a triple dose intravenous injection of the contrast agents. The P792 and Gd-DOTA were equivalent in their ability to demonstrate PE as perfusion defects on first pass imaging. The signal from P792 was significantly higher in vasculature than that from Gd-DOTA between the first and the tenth minutes after injection. The results suggest that a CE-MRA PE could be reliably diagnosed up to 15 minutes after injection. P792 is superior to Gd-DOTA for the MR diagnosis of PE.

  2. Radiolabelled of c-DOTA-RGD and c-DOTA-RGDf with 177Lu and evaluation in vitro and in vivo stability

    Integrin αvβ3 has a critical role in tumor angio genesis and metastasis. Radiolabelled peptides based on the Arg-Gly-Asp (RGD) sequence have been reported as radiopharmaceuticals with high affinity and selectivity for the αvβ3 integrin. The aim of this study was to label c-DOTA-RGD and c-DOTA-RGDf peptides with 177Lu and to evaluate their in vitro and in vivo stability as potential specific therapeutic radiopharmaceuticals. Labelled was carried out by direct reaction of 177LuCl3 with c-DOTA-RGD peptides in 1 M acetate buffer ph 5.5 at 90o C for 30 min. Radiochemical purity and stability studies were realized by reversed phase HPLC and I TLC-Sg analyses in human serum and saline solution. Biological recognition was performed using MCF7 tumor cells (positive αvβ3) and in athymic mice with induced MCF7 tumors. Molecular mechanics and quantum mechanics calculations were performed to explain experimental results associated with the molecular recognition. 177Lu-DOTA-RGD and 177Lu-DOTA-RGDf were obtained with radiochemical purities > 95%, showing adequate in vitro and in vivo stability and specific binding to □v□3 receptors. (Author)

  3. Synthesis and Quantitative Structure-Property Relationships of Side Chain-Modified Hyodeoxycholic Acid Derivatives

    Antimo Gioiello

    2013-08-01

    Full Text Available Bile acids have emerged as versatile signalling compounds of a complex network of nuclear and membrane receptors regulating various endocrine and paracrine functions. The elucidation of the interconnection between the biological pathways under the bile acid control and manifestations of hepatic and metabolic diseases have extended the scope of this class of steroids for in vivo investigations. In this framework, the design and synthesis of novel biliary derivatives able to modulate a specific receptor requires a deep understanding of both structure-activity and structure-property relationships of bile acids. In this paper, we report the preparation and the critical micellization concentration evaluation of a series of hyodeoxycholic acid derivatives characterized by a diverse side chain length and by the presence of a methyl group at the alpha position with respect to the terminal carboxylic acid moiety. The data collected are instrumental to extend on a quantitative basis, the knowledge of the current structure-property relationships of bile acids and will be fruitful, in combination with models of receptor activity, to design and prioritize the synthesis of novel pharmacokinetically suitable ligands useful in the validation of bile acid-responsive receptors as therapeutic targets.

  4. Investigation on inhibition behavior of S-triazole-triazole derivatives in acidic solution

    Four main methods, such as weight loss test, EIS, adsorption isotherm and quantum chemical calculation were employed to study the inhibition efficiency and mechanism of three derivatives on mild steel in acid solution, whose inhibition efficiency were proved to follow the order of DMTT > NMTT > PMTT. The adsorption model of DMTT was established at different temperature according to the fitted results. The quantum chemical results indicated that the adsorption sites of the derivatives were strongly centralized on benzene ring, triazole ring, etc. QSAR was set up to explain the relationship of molecular structure and the inhibition effect of the derivatives

  5. Simultaneous determination of 2-naphthoxyacetic acid and indole-3-acetic acid by first derivation synchronous fluorescence spectroscopy

    Liu, Xiangxiang; Wan, Yiqun

    2013-07-01

    A simple, rapid, sensitive and selective method for simultaneously determining 2-naphthoxyacetic acid (BNOA) and Indole-3-Acetic Acid (IAA) in mixtures has been developed using derivation synchronous fluorescence spectroscopy based on their synchronous fluorescence. The synchronous fluorescence spectra were obtained with Δλ = 100 nm in a pH 8.5 NaH2PO4-NaOH buffer solution, and the detected wavelengths of quantitative analysis were set at 239 nm for BNOA and 293 nm for IAA respectively. The over lapped fluorescence spectra were well separated by the synchronous derivative method. Under optimized conditions, the limits of detection (LOD) were 0.003 μg/mL for BNOA and 0.012 μg/mL for IAA. This method is simple and expeditious, and it has been successfully applied to the determination of 2-naphthoxyacetic acid and indole-3-acetic acid in fruit juice samples with satisfactory results. The samples were only filtrated through a 0.45 μm membrane filter, which was free from the tedious separation procedures. The obtaining recoveries were in the range of 83.88-87.43% for BNOA and 80.76-86.68% for IAA, and the relative standard deviations were all less than 5.0%. Statistical comparison of the results with high performance liquid chromatography Mass Spectrometry (HPLC-MS) method revealed good agreement and proved that there were no significant difference in the accuracy and precision between these two methods.

  6. C-3 benzoic acid derivatives of C-3 deoxybetulinic acid and deoxybetulin as HIV-1 maturation inhibitors.

    Liu, Zheng; Swidorski, Jacob J; Nowicka-Sans, Beata; Terry, Brian; Protack, Tricia; Lin, Zeyu; Samanta, Himadri; Zhang, Sharon; Li, Zhufang; Parker, Dawn D; Rahematpura, Sandhya; Jenkins, Susan; Beno, Brett R; Krystal, Mark; Meanwell, Nicholas A; Dicker, Ira B; Regueiro-Ren, Alicia

    2016-04-15

    A series of C-3 phenyl- and heterocycle-substituted derivatives of C-3 deoxybetulinic acid and C-3 deoxybetulin was designed and synthesized as HIV-1 maturation inhibitors (MIs) and evaluated for their antiviral activity and cytotoxicity in cell culture. A 4-subsituted benzoic acid moiety was identified as an advantageous replacement for the 3'3'-dimethylsuccinate moiety present in previously disclosed MIs that illuminates new aspects of the topography of the pharmacophore. The new analogs exhibit excellent in vitro antiviral activity against wild-type (wt) virus and a lower serum shift when compared with the prototypical HIV-1 MI bevirimat (1, BVM), the first MI to be evaluated in clinical studies. Compound 9a exhibits comparable cell culture potency toward wt virus as 1 (WT EC50=16nM for 9a compared to 10nM for 1). However, the potency of 9a is less affected by the presence of human serum, while the compound displays a similar pharmacokinetic profile in rats to 1. Hence 9a, the 4-benzoic acid derivative of deoxybetulinic acid, represents a new starting point from which to explore the design of a 2nd generation MI. PMID:26968652

  7. Growth behavior of anodic oxide formed by aluminum anodizing in glutaric and its derivative acid electrolytes

    Nakajima, Daiki; Kikuchi, Tatsuya; Natsui, Shungo; Suzuki, Ryosuke O.

    2014-12-01

    The growth behavior of anodic oxide films formed via anodizing in glutaric and its derivative acid solutions was investigated based on the acid dissociation constants of electrolytes. High-purity aluminum foils were anodized in glutaric, ketoglutaric, and acetonedicarboxylic acid solutions under various electrochemical conditions. A thin barrier anodic oxide film grew uniformly on the aluminum substrate by glutaric acid anodizing, and further anodizing caused the film to breakdown due to a high electric field. In contrast, an anodic porous alumina film with a submicrometer-scale cell diameter was successfully formed by ketoglutaric acid anodizing at 293 K. However, the increase and decrease in the temperature of the ketoglutaric acid resulted in non-uniform oxide growth and localized pitting corrosion of the aluminum substrate. An anodic porous alumina film could also be fabricated by acetonedicarboxylic acid anodizing due to the relatively low dissociation constants associated with the acid. Acid dissociation constants are an important factor for the fabrication of anodic porous alumina films.

  8. MR imaging experimental study of intraarticular kinetics of Gd-DOTA

    This paper evaluates the intraarticular kinetics of a paramagnetic MR contrast agent. Imaging parameters and concentration of Gd-DOTA (Guerbet, France) were initially determined by in vitro imaging measurements performed with a 1.5-T magnet. Ten glass tubes of varying concentrations of diluted Gd-DOTA were imaged with different TRs. To optimize the signal intensity differences, the TR was 220 msec with a concentration of 2 mmol/L, 300 mOsm/kg corresponding to the highest signal intensity. Intraarticular injection of 0.8 mL of a 2-mmol/L solution of Gd-DOTA was performed in four Beagle dogs. Sagittal images of the knees were obtained after injection (TR, 220 msec; TE, 20 msec). Measurements of the signal intensity of the joint space were obtained every 5 minutes and validated with two tubes containing water and Gd-DOTA solution (2 mmol/L)

  9. An Unexpected and Efficient Synthesis of Open-chain Derivatives of Bistetronic Acid under Microwave Irradiation

    SHI Feng; MA Ning; ZHOU Dianxiang; ZHANG Ge; JIANG Bo; TU Shujiang

    2009-01-01

    An unexpected and efficient synthesis of novel open-chain derivatives of bistetronic acid has been successfully achieved in glyclol under microwave irradiation (MW).This method has the prominent advantages of short reaction time,high yield,operational simplicity as well as environmental friendliness.

  10. Synthesis of Novel N-9-Substituted Purine Derivatives from Polymer Supported alpha-Amino Acids

    Vanda, D.; Jorda, Radek; Lemrová, B.; Volná, T.; Kryštof, Vladimír; McMaster, C.; Soural, M.

    2015-01-01

    Roč. 17, č. 7 (2015), s. 426-432. ISSN 2156-8952 R&D Projects: GA MŠk(CZ) LO1204; GA MŠk(CZ) LO1304 Institutional support: RVO:61389030 Keywords : alpha-amino acids * solid-phase synthesis * purine derivatives Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.032, year: 2014

  11. Aggregation behavior of cholic acid derivatives in organic solvents and in water

    Willemen, H.M.

    2002-01-01

    In this thesis various cholic acid derivatives are reported that display aggregation in water or in organic solvents. Spontaneous aggregation of single molecules into larger, ordered structures occurs at the borderline of solubility. Amphiphilic compounds, or surfactants, which possess a hydrophobic

  12. Silica Sulfuric Acid: An Eco-Friendly and Reusable Catalyst for Synthesis of Benzimidazole Derivatives

    Bahareh Sadeghi

    2013-01-01

    Full Text Available Silica sulfuric acid (SiO2-OSO3H as an eco-friendly, readily available, and reusable catalyst is applied to benzimidazole derivatives synthesis under reflux in ethanol. The procedure is very simple and the products are isolated with an easy workup in good-to-excellent yields.

  13. Heterogeneous catalysts for the transformation of fatty acid triglycerides and their derivatives to fuel hydrocarbons

    The results of studies devoted to the catalysts for transformation of fatty acid triglycerides and their derivatives to fuel hydrocarbons are presented and described systematically. Various approaches to the use of heterogeneous catalysts for the production of biofuel from these raw materials are considered. The bibliography includes 134 references.

  14. Multilayer Film Fabrication and Photoelectric Conversion Property of Two Pyrrolidinofullerene Carboxylic Acid Derivatives

    2000-01-01

    Two multilayer films of pyrrolidinofullerene carboxylic acid derivatives, which exhibit photoelectric conversion property, are reported here. The first monolayers were fabricated on hydrophilic indium-tin-oxide (ITO), quartz, and mica by esterification reaction. The multilayers were characterized by contact angle and UV spectrum. The photoelectric conversion properties of both multilayer films were studied.

  15. An NMR study of merocyanine-type dyes derived from barbituric acid

    Rezende, Marcos Caroli; Flores, Patricio; Guerrero, Juan; Villarroel, Luis

    2004-06-01

    The 13C NMR of two solvatochromic dyes derived from a barbituric acid acceptor and dimethylaminophenyl donor fragments, compound 1 and the related merocyanine 2, were recorded in various solvents. The observed chemical-shift variations were used to interpret their structural differences and solvatochromic behavior in solution.

  16. Spiro-annulation of barbituric acid derivatives and its analogs by ring-closing metathesis reaction.

    Kotha, Sambasivarao; Deb, Ashoke Chandra; Kumar, Ramanatham Vinod

    2005-02-15

    Barbituric acid 1 and related beta-dicarbonyl compounds were dialkenylated under the phase-transfer catalyst [e.g., benzyltriethylammonium chloride (BTEAC)] conditions to generate the diallylated products. These diallylated products were subjected to the ring-closing metathesis (RCM) reaction to deliver the corresponding spiro-annulated derivatives. PMID:15686908

  17. Substrate-specific effects of pirinixic acid derivatives on ABCB1-mediated drug transport.

    Michaelis, Martin; Rothweiler, Florian; Wurglics, Mario; Aniceto, Natália; Dittrich, Michaela; Zettl, Heiko; Wiese, Michael; Wass, Mark; Ghafourian, Taravat; Schubert-Zsilavecz, Manfred; Cinatl, Jindrich

    2016-03-01

    Pirinixic acid derivatives, a new class of drug candidates for a range of diseases, interfere with targets including PPARα, PPARγ, 5-lipoxygenase (5-LO), and microsomal prostaglandin and E2 synthase-1 (mPGES1). Since 5-LO, mPGES1, PPARα, and PPARγ represent potential anti-cancer drug targets, we here investigated the effects of 39 pirinixic acid derivatives on prostate cancer (PC-3) and neuroblastoma (UKF-NB-3) cell viability and, subsequently, the effects of selected compounds on drug-resistant neuroblastoma cells. Few compounds affected cancer cell viability in low micromolar concentrations but there was no correlation between the anti-cancer effects and the effects on 5-LO, mPGES1, PPARα, or PPARγ. Most strikingly, pirinixic acid derivatives interfered with drug transport by the ATP-binding cassette (ABC) transporter ABCB1 in a drug-specific fashion. LP117, the compound that exerted the strongest effect on ABCB1, interfered in the investigated concentrations of up to 2μM with the ABCB1-mediated transport of vincristine, vinorelbine, actinomycin D, paclitaxel, and calcein-AM but not of doxorubicin, rhodamine 123, or JC-1. In silico docking studies identified differences in the interaction profiles of the investigated ABCB1 substrates with the known ABCB1 binding sites that may explain the substrate-specific effects of LP117. Thus, pirinixic acid derivatives may offer potential as drug-specific modulators of ABCB1-mediated drug transport. PMID:26887049

  18. Molecular markers derived from bombesin for tumor diagnosis by SPECT and PET; Marcadores moleculares derivados da bombesina para diagnostico de tumores por SPECT e PET

    Pujatti, Priscilla Brunelli

    2012-07-01

    A high number of molecules have already been identified to have high affinity to some receptors overexpressed on tumour cells and the radiolabelling of those molecules offers the possibility of new compounds for tumour diagnosis and therapy by nuclear medicine. Among of those molecules, bombesin (BBN) has become focus of interest, as its BB{sub 2} receptors are known to be overexpressed in prostate, breast, colon, pancreatic and lung tumour, as long as glioblastomas and neuroblastomas. BBN agonists and antagonists have already been described for this purpose and promising results were obtained in preclinical studies. However, most of them exhibited high abdominal accumulation, especially in pancreas and intestines, which can compromise diagnosis accuracy and cause serious adverse effects in therapy. In this context, the goal of the present work to radiolabel new BBN derivatives with {sup 11}1In and {sup 68}Ga and to evaluate their potential for BB{sub 2} positive tumors diagnosis by single photon emission tomography (SPECT) and positron emission tomography (PET). The structure of studied peptides was Q-YG{sub n}-BBN(6-14), where Q is the chelator, n is the number of glycine aminoacids in the spacer YG{sub n} and BBN(6-14) is the original bombesin sequence from the aminoacid 6 to 14. The derivative in which the last aminoacid (methionine, Met) was replaced by norleucine (Nle) was also evaluated. The experimental evaluation of the bombesin derivatives was divided into four steps: computational studies, molecular markers for SPECT, molecular markers for PET and toxicological studies. The theoretical partition (log P) and distribution (log D) coefficients were calculated for all bombesin derivatives conjugated to DTPA (diethylenetriaminepentaacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelators applying computational programmes. Bombesin derivatives for SPECT were developed by radiolabelling DTPA-conjugated bombesin derivatives with

  19. Polyhydroxyalkanoate-based 3-hydroxyoctanoic acid and its derivatives as a platform of bioactive compounds.

    Radivojevic, Jelena; Skaro, Sanja; Senerovic, Lidija; Vasiljevic, Branka; Guzik, Maciej; Kenny, Shane T; Maslak, Veselin; Nikodinovic-Runic, Jasmina; O'Connor, Kevin E

    2016-01-01

    A library of 18 different compounds was synthesized starting from (R)-3-hydroxyoctanoic acid which is derived from the bacterial polymer polyhydroxyalkanoate (PHA). Ten derivatives, including halo and unsaturated methyl and benzyl esters, were synthesized and characterized for the first time. Given that (R)-3-hydroxyalkanoic acids are known to have biological activity, the new compounds were evaluated for antimicrobial activity and in vitro antiproliferative effect with mammalian cell lines. The presence of the carboxylic group was essential for the antimicrobial activity, with minimal inhibitory concentrations against a panel of bacteria (Gram-positive and Gram-negative) and fungi (Candida albicans and Microsporum gypseum) in the range 2.8-7.0 mM and 0.1-6.3 mM, respectively. 3-Halogenated octanoic acids exhibited the ability to inhibit C. albicans hyphae formation. In addition, (R)-3-hydroxyoctanoic and (E)-oct-2-enoic acids inhibited quorum sensing-regulated pyocyanin production in the opportunistic pathogen Pseudomonas aeruginosa PAO1. Generally, derivatives did not inhibit mammalian cell proliferation even at 3-mM concentrations, while only (E)-oct-2-enoic and 3-oxooctanoic acid had IC50 values of 1.7 and 1.6 mM with the human lung fibroblast cell line. PMID:26399414

  20. Evaluation of preservative effectiveness of gallic acid derivatives in aluminum hydroxide gel-USP

    Anurag Khatkar

    2013-01-01

    Full Text Available Background: Preservatives are added to most of the pharmaceutical preparations to prevent them from deterioration throughout their shelf life. Literature reveals that the common synthetic preservatives have many limitations, such as development of microbial resistance (in due course of time and several serious side-effects. Aim: The aim of this study is to find out new preservatives synthesized from natural sources, which may have better efficiency than the existing synthetic preservatives. The derivatives of naturally occurring gallic acid were subjected for their preservative efficacy study. Their preservative efficiency was evaluated and compared with the standard parabens. Materials and Methods: The selected amide, anilide and ester derivatives of gallic acid were subjected to preservative efficacy testing in an official antacid preparation, {aluminum hydroxide gel-USP (United States Pharmacopoeia} against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans, and Aspergillus niger as representative challenging microorganisms as per USP 2004 guidelines. Results: The selected derivatives were found to be effective against all selected strains and showed preservative efficacy comparable to that of standard and even better in case E. coli, C. albicans and A. niger. The 8-hydroxy quinoline ester derivative showed better preservative efficacy than standard as well as other derivatives. Conclusion: The newly synthesized gallic acid preservatives were found to be effective in the proposed pharmaceutical preparation (Aluminium Hydroxide Gel - USP. Also, the synthesized preservatives have shown comparative and even better efficacy than the existing parabens and hence they have potential for use in pharmaceutical preparations.

  1. Evaluation of preservative effectiveness of p-coumaric acid derivatives in aluminium hydroxide gel-USP

    Anurag Khatkar

    2013-01-01

    Full Text Available Background: Deterioration of pharmaceutical preparations due to growth of microorganisms is a great challenge and need of preservation becomes very important. Literature reports about various problems associated with the existing synthetic preservatives such as development of microbial resistance (in due course of time and several serious side effects. Aim: The aim of the present study is to find out new preservatives synthesized from natural sources, which may have better efficiency than the existing synthetic preservatives. The derivatives of naturally occurring p-coumaric acid were subjected for their preservative efficacy study. Their preservative efficiency was evaluated and compared with the standard parabens. Materials and Methods: The selected amide, anilide and ester derivatives of p-coumaric acid were subjected to preservative efficacy testing in an official antacid preparation, (aluminium hydroxide gel-USP against Staphylococcus aureus, Bacillus subtilis, Escherichia coli, Candida albicans and Aspergillus niger as representative challenging microorganisms as per USP 2004 guidelines. Results: The selected derivatives were found to be effective against all selected strains and showed preservative efficacy comparable to that of standard and even better in case E. coli, C. albicans and A. niger. The 8-hydroxy quinoline ester derivative showed better preservative efficacy than standard as well as other derivatives. Conclusion: The newly synthesized p- coumaric acid preservatives were found to be effective in the proposed pharmaceutical preparation (Aluminium Hydroxide Gel - USP. Also, the synthesized preservatives have shown comparative and even better efficacy than the existing parabens and hence they have potential for use in pharmaceutical preparations.

  2. Sm(II)-Mediated Electron Transfer to Carboxylic Acid Derivatives: Development of Complexity-Generating Cascades.

    Just-Baringo, Xavier; Procter, David J

    2015-05-19

    Reductive electron transfer (ET) to organic compounds is a powerful method for the activation of substrates via the formation of radicals, radical anions, anions, and dianions that can be exploited in bond-cleaving and bond-forming processes. Since its introduction to the synthetic community in 1977 by Kagan, SmI2 has become one of the most important reducing agents available in the laboratory. Despite its widespread application in aldehyde and ketone reduction, it was widely accepted that carboxylic acid derivatives could not be reduced by SmI2; only recently has our work led to this dogma being overturned, and the reduction of carboxylic acid derivatives using SmI2 can now take its place alongside aldehyde/ketone reduction as a powerful activation mode for synthesis. In this Account, we set out our studies of the reduction of carboxylic acid derivatives using SmI2, SmI2-H2O, and SmI2-H2O-NR3 and the exploitation of the unusual radical anions that are now accessible in unprecedented carbon-carbon bond-forming processes. The Account begins with our serendipitous discovery that SmI2 mixed with H2O is able to reduce six-membered lactones to diols, a transformation previously thought to be impossible. After the successful development of selective monoreductions of Meldrum's acid and barbituric acid heterocyclic feedstocks, we then identified the SmI2-H2O-NR3 reagent system for the efficient reduction of a range of acyclic carboxylic acid derivatives that typically present a significant challenge for ET reductants. Mechanistic studies have led us to propose a common mechanism for the reduction of carboxylic acid derivatives using Sm(II), with only subtle changes observed as the carboxylic acid derivative and Sm(II) reagent system are varied. At the center of our postulated mechanism is the proposed reversibility of the first ET to the carbonyl of carboxylic acid derivatives, and this led us to devise several strategies that allow the radical anion intermediates to be

  3. Radiolabelled DOTA-TATE: Its evaluation for targeted radiotherapy

    The development of a radiopharmaceutical for cancer therapy based on a somatostatin analog peptide DOTATATE (DOTA-D-phe-cys-tyr-D-trp-lys-thr-cys-thr) labelled with I-125 was done and the biological properties were investigated. Labelling of the DOTA-TATE was achieved by oxidation of iodide with Chloramine-T. Purification was done by C18 separation cartridge using ethanol as the eluent and further reverse-phase chromatography (HPLC) on the eluate to increase specific activity. Stability of the labelled peptide at different time intervals as well as storing conditions was evaluated by RPHPLC and by chromatography in ITLC-SG or Whatman 3MM using different mobile phases: 2-butanone (MEK); NaCl 0.9%; EtOH-HCl 0.01N 90:10 and butanol:acetic:H O (4:1:5) (2). Also, electrophoresis was 2 done on Whatman 1 with Tris buffer, (pH 7.5, 200V, 80mA, 45 min). Biological behaviour of I-125 DOTA-TATE was evaluated through interaction with somatostatin receptors extracted from rat cortex membranes as well as from AR4- 2J cell membranes. In vitro binding of the peptide to viable AR4-2J was evaluated through internalization studies. The labelling yield obtained was higher than 95%. HPLC profile revealed that two radiochemical species were present having retention times of 23.5 and 25.0 min, while the unlabelled peptide eluted at 21.0 min. I-125 DOTATATE was obtained with very high yield even prior purification. The two radiochemical species evidenced by RP-HPLC could be interpreted as mono and diiodinated radio-conjugate species. Their retention times are slightly higher than the intact unlabelled peptide allowing the preparation of a labelled molecule with high specific activity. Stability of the radio-conjugate (at -4 deg. C and -80 deg. C) was determined over a period of more than 8 days. Maximum binding capacity (MBC) was found to be 23% for the species eluted at 25 min. Also MBC was lower for receptors obtained from AR 42J cells. 50% Inhibition dose was 9μg/mL (CV 20%). The

  4. Influence of organic acids on UV-Vis spectra of pyrrolidino- [60]fullerene derivatives

    2001-01-01

    A pyrrolidino[60]fullerene 1 with pyrrolidine group was synthesized and characterized. The UV-Vis spectra showed that the blue shift of absorption peaks was first observed when strong organic acids such as p-toluene sulfonic or trifluoroacetic acid were added to the solution of pyrrolidino[60]fullerene 1 in dichloromethane. The results indicated that the pyrrolidino[60]fullerene derivatives without pyrrolidine group also possess the same phenomenon. Experiments and computation with the MOPAC 7.0 semi-em- pirical PM3 method demonstrated the reason that some energy gaps on [60]fullerene skeleton were increased because electronic charges on [60]fullerene framework transferred to pyrrolidine ring when strong organic acids were added into pyrrolidino[60]fullerene derivatives' solution; as the result, the complexes could be formed and some absorption wave-lengths blue shifted in the UV-Vis spectrum.

  5. [The influence of docosahexaenoic acid moiety on cytotoxic activity of 1,2,4-thiadiazole derivatives].

    Akimov, M G; Gretskaia, N M; Karnoukhova, V A; Serkov, I V; Proshin, A N; Shtratnikova, V Iu; Bezuglov, V V

    2014-01-01

    Among 3-(2-aminopropyl)-1,2,4-thiadiazole derivatives contatining substitution-ready secondary amino group and exhibiting cytotoxic towards rat C 6 glioma cells three compounds with LD 50 values ranged from 6 to 48 мM were chosen. For these compounds amides with docosahexaenoic acid were synthetised and their cytotoxic activity was studied. It was shown that, although docosahexaenoic acid itself was not toxic for C 6 glioma cells, its addition to the amino derivatives of 1,2,4-thiadiazole increased or decreased resultant cytotoxicity. The effect depended on the structure of 1,2,4-thiadiazole substituents. The obtained data show that the acylation of cytotoxic compounds with docosahexaenoic acid does not necessarily lead to the increase of their activity, but sometimes can inactivate a compound. This fact should be taken into account, especially in the case of anti-cancer drug development. PMID:25249531

  6. Radiolabeling parameters of {sup 177}Lu-DOTA-RITUXIMAB

    Massicano, Adriana V.F.; Alcarde, Lais F.; Oliveira, Ricardo S.; Mengatti, Jair; Araujo, Elaine B. de, E-mail: adriana.avfernandes@gmail.com [Instituto de Pesquisas Energeticas e Nucleares (IPEN/CNEN-SP), Sao Paulo, SP (Brazil)

    2013-07-01

    Cancer treatment using radioimmunotherapy (RIT) has been the focus of much research in the last two decades. In RIT, a radioisotope is coupled to a monoclonal antibody (mAb) to form a tumor-specific target agent to improve the cytocidal effect of the mAbs. RIT allows the systemic delivery of radiation to disease target by mAbs while sparing normal tissues. Rituximab® (Mabthera - Roche) is a chimeric mouse-human monoclonal antibody; it selectively binds with high affinity to the CD20 antigen, a hydrophobic transmembrane protein, which is expressed on B-lymphocytes and in more than 90% of B cell non-Hodgkin's lymphomas (NHL). The conjugation and radiolabeling process involve special conditions of pH and temperature, long processes of manipulation and mixing. All this process can damage the antibody structure and compromise its clinical application. Therefore, these parameters must be largely studied. The aim of this work was to evaluate the best radiolabeling conditions of DOTA-rituximab. Briefly, 10 mg of antibody previously purified by ultrafiltration device was conjugated with DOTA-NHS-ester (Macrocyclics) in 50 fold molar excess. The reaction was conducted for 1 hour in phosphate buffer pH 8.0 and gently mixing at room temperature, remaining for 24 hours under refrigeration. The immunoconjugated was purified by size exclusion column and ultrafiltration device. The radiolabeled parameters studied were: immunoconjugated mass, activity of {sup 177}LuCl{sub 3}, reaction time, temperature and pH. The radiochemical purity of the preparations was determined using analysis by thin layer chromatography (TLC-SG plates). The best studied condition presented radiochemical purity above 95% and the integrity of antibody was preserved. (author)

  7. RNA:DNA Ratio and Other Nucleic Acid Derived Indices in Marine Ecology

    Luis Chícharo

    2008-08-01

    Full Text Available Some of most used indicators in marine ecology are nucleic acid-derived indices. They can be divided by target levels in three groups: 1 at the organism level as ecophysiologic indicators, indicators such as RNA:DNA ratios, DNA:dry weight and RNA:protein, 2 at the population level, indicators such as growth rate, starvation incidence or fisheries impact indicators, and 3 at the community level, indicators such as trophic interactions, exergy indices and prey identification. The nucleic acids derived indices, especially RNA:DNA ratio, have been applied with success as indicators of nutritional condition, well been and growth in marine organisms. They are also useful as indicators of natural or anthropogenic impacts in marine population and communities, such as upwelling or dredge fisheries, respectively. They can help in understanding important issues of marine ecology such as trophic interactions in marine environment, fish and invertebrate recruitment failure and biodiversity changes, without laborious work of counting, measuring and identification of small marine organisms. Besides the objective of integrate nucleic acid derived indices across levels of organization, the paper will also include a general characterization of most used nucleic acid derived indices in marine ecology and also advantages and limitations of them. We can conclude that using indicators, such RNA:DNA ratios and other nucleic acids derived indices concomitantly with organism and ecosystems measures of responses to climate change (distribution, abundance, activity, metabolic rate, survival will allow for the development of more rigorous and realistic predictions of the effects of anthropogenic climate change on marine systems.

  8. Theoretical investigation on the geometries of DOTA and DOTA-like complexes and on the transition states of their conformational equilibria

    Computations, mostly at the RHF level, have been performed on La3+ and Y3+ model complexes of the widely used DOTA ligand [DOTA 1,4,7,10-tetra-aza-1,4,7,10-tetrakis(carboxy-methyl)cyclo-dodecane] for the purpose of identifying properties of the transition states of geometrical isomer inter-conversions, which have been the object of numerous NMR studies. An analogous study has been carried out on model complexes of the same tri-cations formed by the DOTA-like ligand 1,7-bis(1-methyl-imidazole-2-ylmethyl)-4,10-bis(carboxy-methyl)-1 4,7,10-tetra-aza-cyclo-dodecane, LH2. Features of the transition states for the two types of systems are compared. (authors)

  9. Potential biological applications of bio-based anacardic acids and their derivatives.

    Hamad, Fatma B; Mubofu, Egid B

    2015-01-01

    Cashew nut shells (CNS), which are agro wastes from cashew nut processing factories, have proven to be among the most versatile bio-based renewable materials in the search for functional materials and chemicals from renewable resources. CNS are produced in the cashew nut processing process as waste, but they contain cashew nut shell liquid (CNSL) up to about 30-35 wt. % of the nut shell weight depending on the method of extraction. CNSL is a mixture of anacardic acid, cardanol, cardol, and methyl cardol, and the structures of these phenols offer opportunities for the development of diverse products. For anacardic acid, the combination of phenolic, carboxylic, and a 15-carbon alkyl side chain functional group makes it attractive in biological applications or as a synthon for the synthesis of a multitude of bioactive compounds. Anacardic acid, which is about 65% of a CNSL mixture, can be extracted from the agro waste. This shows that CNS waste can be used to extract useful chemicals and thus provide alternative green sources of chemicals, apart from relying only on the otherwise declining petroleum based sources. This paper reviews the potential of anacardic acids and their semi-synthetic derivatives for antibacterial, antitumor, and antioxidant activities. The review focuses on natural anacardic acids from CNS and other plants and their semi-synthetic derivatives as possible lead compounds in medicine. In addition, the use of anacardic acid as a starting material for the synthesis of various biologically active compounds and complexes is reported. PMID:25894225

  10. Potential Biological Applications of Bio-Based Anacardic Acids and Their Derivatives

    Fatma B. Hamad

    2015-04-01

    Full Text Available Cashew nut shells (CNS, which are agro wastes from cashew nut processing factories, have proven to be among the most versatile bio-based renewable materials in the search for functional materials and chemicals from renewable resources. CNS are produced in the cashew nut processing process as waste, but they contain cashew nut shell liquid (CNSL up to about 30–35 wt. % of the nut shell weight depending on the method of extraction. CNSL is a mixture of anacardic acid, cardanol, cardol, and methyl cardol, and the structures of these phenols offer opportunities for the development of diverse products. For anacardic acid, the combination of phenolic, carboxylic, and a 15-carbon alkyl side chain functional group makes it attractive in biological applications or as a synthon for the synthesis of a multitude of bioactive compounds. Anacardic acid, which is about 65% of a CNSL mixture, can be extracted from the agro waste. This shows that CNS waste can be used to extract useful chemicals and thus provide alternative green sources of chemicals, apart from relying only on the otherwise declining petroleum based sources. This paper reviews the potential of anacardic acids and their semi-synthetic derivatives for antibacterial, antitumor, and antioxidant activities. The review focuses on natural anacardic acids from CNS and other plants and their semi-synthetic derivatives as possible lead compounds in medicine. In addition, the use of anacardic acid as a starting material for the synthesis of various biologically active compounds and complexes is reported.

  11. Synthesis of benzamide derivatives of anacardic acid and their cytotoxic activity.

    Chandregowda, Venkateshappa; Kush, Anil; Reddy, Goukanapalli Chandrasekara

    2009-06-01

    Several benzamide derivatives were synthesized from anacardic acid (1a) which was the product of hydrogenation of the naturally occurring anacardic acid mixture (1a-d), a major constituent of cashew nut shell liquid. Anacardic acid (1a) was first alkylated followed by hydrolysis of the ester to obtain synthones namely, 2-ethoxy-6-pentadecylbenzoic acid (5) and 2-isopropoxy-6-pentadecylbenzoic acid (6). These salicylic acid derivatives were then coupled with a variety of anilines to obtain novel benzamide compounds (7-39). Cytotoxic effect of these synthesized compounds was tested on HeLa cell line of wild type with relatively high expression of p300 and on HCT-15, which is p300 negative. Of all the compounds, 2-isopropoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (27), 2-ethoxy-N-(3-nitrophenyl)-6-pentadecylbenzamide (22) and 2-ethoxy-6-pentadecyl-N-pyridin-4-ylbenzamide (10) were found to be more potent with the respective IC(50) values 11.02 microM, 13.55 microM, 15.29 microM on HeLa cell line. Their activities are comparable with garcinol which is a cell permeable histone acetyltransferase (HAT) inhibitor and 10 fold more active than p300 HAT activators so far reported. PMID:19246131

  12. of radioconjugated DOTA-1-Nal3-octreotide labeled with gallium-68 using non-aqueous solvents

    Neuroendocrine tumors specifically over-expressing somatostatin receptors. Diagnosis has expanded due to radiolabelling of DOTA-peptides such as somatostatin analogue DOTA-1-Nal3-Octreotide (DOTA-NOC) conjugated to β+ emitting radionuclides such as 68Ga, which has very favorable physics-nuclear properties. This paper describes the radiolabeling procedures of DOTA-NOC with 68Ga, in pure aqueous medium and in presence of non-aqueous solvents as well as the methods used for quality control where a formulation is obtained with a radiochemical yield exceeding 95%. The addition of ethanol (30% - v / v) to reaction mixture allowed to increase the specific activity of 68Ga-DOTA-NOC radioconjugate, reaching a value of 182 MBq / nmol, higher than reported in the literature (50 MBq / nmol ) for labeling in pure aqueous medium. Stability studies are also presented (in presence of saline solution and saline phosphate buffer, transmetallation studies in Fe3+, Ca2+, Mg2+ and Zn2+ solutions, challenges competition against EDTA and DTPA chelators and in vitro stability in human transferrin) performed to 68Ga-DOTA-NOC radioconjugated, showing its high stability (> 95%). (author)

  13. Pantothenic acid and its derivatives protect Ehrlich ascites tumor cells against lipid peroxidation.

    Slyshenkov, V S; Rakowska, M; Moiseenok, A G; Wojtczak, L

    1995-12-01

    Preincubation of Ehrlich ascites tumor cells at 22 or 32 degrees C, but not at 0 degree C, with pantothenic acid, 4'-phosphopantothenic acid, pantothenol, or pantethine reduced lipid peroxidation (measured by production of thiobarbituric acid-reactive compounds) induced by the Fenton reaction (Fe2+ + H2O2) and partly protected the plasma membrane against the leakiness to cytoplasmic proteins produced by the same reagent. Pantothenic acid and its derivatives did not inhibit (Fe2+ + H2O2)-induced peroxidation of phospholipid multilamellar vesicles, thus indicating that their effect on the cells was not due to the scavenging mechanism. Homopantothenic acid and its 4'-phosphate ester (which are not precursors of CoA) neither protected Ehrlich ascites tumor cells against lipid peroxidation nor prevented plasma membrane leakiness under the same conditions. Incubation of the cells with pantothenic acid, 4'-phosphopantothenic acid, pantothenol, or pantethine significantly increased the amount of cellular CoA and potentiated incorporation of added palmitate into phospholipids and cholesterol esters. It is concluded that pantothenic acid and its related compounds protect the plasma membrane of Ehrlich ascites tumor cells against the damage by oxygen free radicals due to increasing cellular level of CoA. The latter compound may act by diminishing propagation of lipid peroxidation and promoting repair mechanisms, mainly the synthesis of phospholipids. PMID:8582649

  14. Effect of root derived organic acids on the activation of nutrients in the rhizosphere soil

    2002-01-01

    Four types of soils, including brown coniferous forest soil, dark brown soil, black soil, and black calic soil, sampled from three different places in northeast China were used in this test. The functions of two root-derived organic acids and water were simulated and compared in the activation of mineral nutrients from the rhizosphere soil. The results showed that the organic acids could activate the nutrients and the activated degree of the nutrient elements highly depended on the amount and types of the organic acid excreted and on the physiochemical and biochemical properties of the soil tested. The activation effect of the citric acid was obviously higher than that of malic acid in extracting Fe, Mn, Cu, and Zn for all the tested soil types. However, the activation efficiencies of P, K, Ca, and Mg extracting by the citric acid were not much higher, sometimes even lower, than those by malic acid. The solution concentration of all elements increased with increase of amount of the citric acid added.

  15. Syntheses,characteristics and fluorescence properties of complexes of terbium with benzoic acid and its derivatives

    ZHOU Zhong-cheng; SHU Wan-gen; RUAN Jian-ming; HUANG Bai-yun; LIU You-nian

    2005-01-01

    The binary complexes of terbium with benzoic acid and its derivatives (phthalic acid,iso-phthalic acid,oaminobenzoic acid,salicylic acid,sulfosalicylic acid) were synthesized and their compositions were identified by elemental analyses.UV,IR of the complexes were investigated.The UV spectra indicate that the complexes'ultraviolet absorption is mainly the ligands' absorption,but the location of peak drifts.The IR spectra show that the IR spectra of complexes are different from those of free ligands,and the band at 400-500 cm-1,due to the stretching vibration of Tb-O,is absent for free ligands.The fluorescence properties were investigated by using luminescence spectroscope,the results show that all the six complexes of terbium exhibit excellent luminescence,due to the transition from the lowest excited state 5D4 to 7F ground state manifold,the complexes of terbium with sulfosalicylic acid have the strongest fluorescence intensity,and is stronger than o-aminobenzoic acid-terbium,whose fluorescence intensity is regarded as the strongest one in the literature,and even stronger than some phosphor of terbium.

  16. Synthesis of 2-phenyl- and 2,3-diphenyl-quinolin-4-carboxylic acid derivatives

    Quinolin derivatives are a group of compounds known to possess a wide range of biological activities. The chemistry of quinolines together with their corresponding aldehydes were dealt with in chapter one of this study. Special emphasis was given to the chemistry of benzaldehyde. Twenty five 2-phenyl- and 2,3-diphenyl-quinolin-4-carboxylic acid derivatives together with their corresponding intermediates were prepared in this work. Basically, the synthetic design of these compounds arise from the appropriate disconnections of the target 2-phenyl and 2,3-diphenyl-quinolin-4-carboxylic acids. The retro synthesis analysis of these compounds reveals pyruvic acid, aromatic amine and benzaldehyde or phenyl pyruvic acid, aromatic amine and benzaldehyde as possible logical precursors for 2-phenyl-and 2,3-diphenyl- quinoline-4-carboxylic acids respectively. The purity and identities of the synthesized compounds were elucidated through chromatographic and spectroscopic techniques. The compounds were heavily subjected to spectroscopic analysis (UV, IR, GC/MS, 1H-and 13C- NMR). The appropriate disconnections and the mechanisms of the corresponding reactions were given and discussed in chapter three. The spectral data were interpreted and correlated with the target structures. The prepared 2-phenyl- and 2,3-diphenyl-quinoline-4-carboxylic acid derivatives were screened for their antibacterial activity. The compounds were tested against the standard bacterial organisms B. subtilis, S. aureus, E. coli and P. vulgaris. Some of these compounds were devoid of antibacterial activity against S. aureus and P. vulgaris, while others showed moderate activity. All of the tested compounds showed an activity against B. subtilis and E. coli. 2,3-diphenyl -6-sulphanilamide-quinolin-4-carboxylic acid showed the highest activity against the four standard tested organisms.(Author)

  17. Gastroprotective Mechanisms of Action of Semisynthetic Carnosic Acid Derivatives in Human Cells

    Cristina Theoduloz

    2014-01-01

    Full Text Available Carnosic acid (CA and its semisynthetic derivatives display relevant gastroprotective effects on HCl/ethanol induced gastric lesions in mice. However, little is known on the mechanisms of action of the new compounds. The aim of the present work was to assess the gastroprotective action mechanisms of CA and its derivatives using human cell culture models. A human gastric adenocarcinoma cell line (AGS and lung fibroblasts (MRC-5 were used to reveal the possible mechanisms involved. The ability of the compounds to protect cells against sodium taurocholate (NaT-induced damage, and to increase the cellular reduced glutathione (GSH and prostaglandin E2 (PGE2 content was determined using AGS cells. Stimulation of cell proliferation was studied employing MRC-5 fibroblasts. Carnosic acid and its derivatives 10–18 raised GSH levels in AGS cells. While CA did not increase the PGE2 content in AGS cells, all derivatives significantly stimulated PGE2 synthesis, the best effect being found for the 12-O-indolebutyrylmethylcarnosate 13. A significant increase in MRC-5 fibroblast proliferation was observed for the derivatives 7 and 16–18. The antioxidant effect of the compounds was assessed by the inhibition of lipid peroxidation in human erythrocyte membranes, scavenging of superoxide anion and DPPH discoloration assay. The new CA derivatives showed gastroprotective effects by different mechanisms, including protection against cell damage induced by NaT, increase in GSH content, stimulation of PGE2 synthesis and cell proliferation.

  18. Comparison of 131I-TYR3-octreotate and 131I-DOTA-TYR3-octreotate: The effect of DOTA on pharmacokinetics and stability

    The authors compared the biodistribution, and in vivo and in vitro stabilities of 131I-Tyr3-octreotate and 131I-DOTA-Tyr3-octreotate. The peptides were radioiodinated by the chloramine T method and high radiochemical yields were obtained (greater than 97%). Both labelled compounds showed high stability when incubated in human plasma at 37 deg C. The 131I-Tyr3-octreotate showed significant hepatic uptake and biliary excretion. The biodistribution of 131I-DOTA-Tyr3-octreotate, however, can be compared with the distribution of radiometal labelled octreotide analogues. (author)

  19. Chiral trans-1,2-diaminocyclohexane derivatives as chiral solvating agents for carboxylic acids

    Mariappan Periasamy; Manasi Dalai; Meduri Padmaja

    2010-07-01

    Efficient use of the readily accessible chiral 2-symmetric acyclic diamines (1-2) as well as macrocyclic amines (3-5) containing trans-1,2-diaminocyclohexyl moiety as chiral solvating agents (CSA) for the determination of enantiomeric excess of representative carboxylic acids (6-7) and an amino acid derivative (8) is illustrated. The enantiomeric composition of different carboxylic acids estimated here by the 1H NMR method, based on the integration of the corresponding methine proton signals are in good correlation with that determined using HPLC method. The data are in accordance with the formation of multimolecular diastereomeric complexes in solution, which render good splitting of NMR signals for the enantiomers of representative carboxylic acids as well as for -Ts-phenylglycine (up to = 0.295 ppm, 118 Hz).

  20. MOF-Derived Tungstated Zirconia as Strong Solid Acids toward High Catalytic Performance for Acetalization.

    Wang, Peng; Feng, Jian; Zhao, Yupei; Wang, Shaobin; Liu, Jian

    2016-09-14

    A strong solid acid, tungstated zirconia (WZ), has been prepared first using tungstate immobilized UiO-66 as precursors through a "double-solvent" impregnation method under mild calcination temperature. With moderate W contents, the as-synthesized WZ catalysts possess a high density of acid sites, and the proper heat treatment also has facilely led to a bunch of oligomeric tungsten clusters on stabilized tetragonal ZrO2. The resultant solid acids show an improved catalytic performance toward the benzaldehyde's acetalization in comparison with traditional zirconium hydroxide-prepared WZ. Notably, due to large surface area and additionally introduced strong acid sites, the MOF-derived WZ catalysts afforded conversion up to 86.0%. The facile method endows the WZ catalysts with superior catalytic activities and excellent recyclability, thus opening a new avenue for preparation of metal oxide-based solid superacids and superbases. PMID:27557351

  1. Extraction of gold, palladium, and platinum from acidic media with cyclic sulfoxide derivative

    Songping Wu; Guobang Gu

    2007-01-01

    The extraction of gold (Ⅲ), palladium (Ⅱ), and platinum (Ⅳ) from the acidic media with the cyclic sulfoxide derivative of a-dodecyl-tetrahydrothiophene 1-oxide (dtmso) was investigated. Gold (Ⅲ), palladium (Ⅱ), and platinum (Ⅳ) could be separated from the acidic media with suitable sulfoxide concentration and acidity. The extraction reaction of gold (Ⅲ), palladium (Ⅱ) or platinum (Ⅳ) is exothermic when dtmso is used as an extracting reagent. The coordination number was studied by the slope method. The results indicate that, in high acidity, the dtmso coordination number for extracting gold (Ⅲ) or palladium (Ⅱ) is 3, and that for platinum (Ⅳ) is 2. UV and FT-IR spectra were used to analyze the structure of the complex. Gold (Ⅲ) is coordinated with the oxygen atom in S=O group in dtmso, and palladium (Ⅱ) or platinum (Ⅳ) is coordinated with the sulfur atom in S=O group in dtmso.

  2. EIMS Fragmentation Pathways and MRM Quantification of 7α/β-Hydroxy-Dehydroabietic Acid TMS Derivatives

    Rontani, Jean-François; Aubert, Claude; Belt, Simon T.

    2015-09-01

    EI mass fragmentation pathways of TMS derivatives οf 7α/β-hydroxy-dehydroabietic acids resulting from NaBH4-reduction of oxidation products of dehydroabietic acid (a component of conifers) were investigated and deduced by a combination of (1) low energy CID-GC-MS/MS, (2) deuterium labeling, (3) different derivatization methods, and (4) GC-QTOF accurate mass measurements. Having identified the main fragmentation pathways, the TMS-derivatized 7α/β-hydroxy-dehydroabietic acids could be quantified in multiple reaction monitoring (MRM) mode in sea ice and sediment samples collected from the Arctic. These newly characterized transformation products of dehydroabietic acid constitute potential tracers of biotic and abiotic degradation of terrestrial higher plants in the environment.

  3. The influence of humic acids derived from earthworm-processed organic wastes on plant growth

    Atiyeh, R.M.; Lee, S.; Edwards, C.A.; Arancon, N.Q.; Metzger, J.D. [Ohio State University, Columbus, OH (United States). Soil Ecology Lab.

    2002-08-01

    Some effects of humic acids, formed during the breakdown of organic wastes by earthworms (vermicomposting), on plant growth were evaluated. In the first experiment, humic acids were extracted from pig manure vermicompost using the classic alkali/acid fractionation procedure and mixed with a soilless container medium (Metro-Mix 360), to provide a range of 0, 50, 100, 150, 200, 250, 500, 1000, 2000 and 4000 mg of humate per kg of dry weight of container medium, and tomato seedlings were grown in the mixtures. In the second experiment, humates extracted from pig manure and food wastes vermicomposts were mixed with vermiculite to provide a range of 0, 50, 125, 250, 500, 1000 and 4000 mg of humate per kg of dry weight of the container medium, and cucumber seedlings were grown in the mixtures. Both tomato and cucumber seedlings were watered daily with a solution containing all nutrients required to ensure that any differences in growth responses were not nutrient-mediated. The incorporation of both types of vermicompost-derived humic acids, into either type of soilless plant growth media, increased the growth of tomato and cucumber plants significantly, in terms of plant heights, leaf areas, shoot and root dry weights. Plant growth increased with increasing concentrations of humic acids incorporated into the medium up to a certain proportion, but this differed according to the plant species, the source of the vermicompost, and the nature of the container medium. Plant growth tended to be increased by treatments of the plants with 50-500 mg/kg humic acids, but often decreased significantly when the concentrations of humic acids derived in the container medium exceeded 500-1000 mg/kg. These growth responses were most probably due to hormone-like activity of humic acids from the vermicomposts or could have been due to plant growth hormones adsorbed onto the humates. (author)

  4. Radiopharmacology of iminodiacetic acid N-derivatives analysis in biological models and comparison to human beings

    It was studied the influence of chemical structures and molecular weight in the distribution of several iminodiacetic acid N-derivatives and to determine the potential use of these radiopharmaceuticals in humans. The study was performed with the following derivatives: N-(2,6 dimetyphenylcarbamoylmethy) iminodiacetic acid, N(2.6 dietylphenyl-carbamoylmethy) iminodiacetic acid, N-(2,6 diisopropylphenylcarbamoylmethy) iminodiacetic acid and the previously unknown N-derivative N-(2,6 diisopropyl, phenylcarbamoylethyl) iminodiacetic aced. These were sinthesized by a modified procedure by MITTA et al. and controlled by NMR, mass spectrometry, elemental composition and also toxicity pirogens, lethal dose and the chelate's radiochemical dose were determined. Liver gallbladder, intestinal and renal kinetics were studied in mice. In order to evaluate the metabolic pathways of the radiopharmaceuticals, the content of gallbladder and the urine were reinjected. Plasma kinetics and the plasmatic half life was determined by extracorporeal circulation in Wistar rats. For the use in human beings, test were carried out in different branches of nuclear medicine, in normal volunteers and carriers of different pathologic disorders. The patients were divided into four groups: acute and chronic cholecystitis, cirrhosis and jaundice. It was obtained the liver/heart activity ratio and estimated the appearance times of the intrahepatic ducts, gallbladder, duodenum and renal persistence. (M.E.L.)

  5. Effect of vanillin and its acid and alcohol derivatives on the diphenolase activity of mushroom tyrosinase

    Masoomeh Bagheri-Kalmarzi

    2012-01-01

    Full Text Available For the first time in the present study the effects of vanillin, vanillyl alcohol, vanillic acid, as well as the newly synthesized vanillin derivative, bis-vanillin, were investigated on the oxidation of dopamine hydrochloride by mushroom tyrosinase. Among them, vanillin and bis-vanillin act as activators, while vanillyl alcohol and vanillic acid exhibited inhibitory effects, the IC50 values being estimated 1.5 and 1.0 mM, respectively. These compounds were mixed inhibitors. The presence of aldehyde and metoxy groups at the meta position of aromatic compounds seems to cause them to react as tyrosinase activators, as observed in the case of vanillin and bis-vanillin. The presence of both groups in bis-vanillin results in a stronger activation effect compared to vanillin. The results indicate that the electron-withdrawing capacity of the functional group at the C-1 position is essential for the inhibitory potency of vanillin derivatives. In comparison with other benzoic acid derivatives, the results obtained in this study suggest that the relative positioning of hydroxy and methoxy groups at meta and para positions plays an important role in the inhibition effects of benzoic acids and their inhibition potency.

  6. Photoaffinity labeling of a bacterial sialidase with an aryl azide derivative of sialic acid

    A photoreactive radioiodinatable derivative of 2-deoxy-2,3-didehydro-5-N-acetylneuraminic acid (NeuAc2en), 5-N-acetyl-9-(4-azidosalicoylamido)-2-deoxy-2,3-didehydroneuram inic acid (ASA-NeuAc2-en) has been synthesized and used to label the active site of Clostridium perfringens sialidase. Like NeuAc2en, its aryl azide derivative is a strong competitive inhibitor of sialidase (Ki approximately 15 microM). The absorbance spectrum of ASA-NeuAc2en shows a characteristic aryl azide peak, which disappears upon photolysis with UV light. When its radioiodinated counterpart 5-N-acetyl-9-(4-iodoazidosalicoylamido)-2-deoxy-2,3-didehydrone uraminic acid ([125I]IASA-NeuAc2en) was photolyzed in the presence of C. perfringens sialidase a 72-kDa protein was labeled. Labeling occurred specifically in the active site since it was inhibited in the presence of NeuAc2en. Chemical cleavage of the photoaffinity-labeled 72-kDa protein demonstrates that specifically labeled peptides involved in the formation of the active site can easily be determined. ASA-NeuAc2en is a valuable new tool for the identification and structural/functional analysis of sialidases and other proteins, recognizing this sialic acid derivative

  7. Carboxylic Acid Fullerene (C60) Derivatives Attenuated Neuroinflammatory Responses by Modulating Mitochondrial Dynamics

    Ye, Shefang; Zhou, Tong; Cheng, Keman; Chen, Mingliang; Wang, Yange; Jiang, Yuanqin; Yang, Peiyan

    2015-05-01

    Fullerene (C60) derivatives, a unique class of compounds with potent antioxidant properties, have been reported to exert a wide variety of biological activities including neuroprotective properties. Mitochondrial dynamics are an important constituent of cellular quality control and function, and an imbalance of the dynamics eventually leads to mitochondria disruption and cell dysfunctions. This study aimed to assess the effects of carboxylic acid C60 derivatives (C60-COOH) on mitochondrial dynamics and elucidate its associated mechanisms in lipopolysaccharide (LPS)-stimulated BV-2 microglial cell model. Using a cell-based functional screening system labeled with DsRed2-mito in BV-2 cells, we showed that LPS stimulation led to excessive mitochondrial fission, increased mitochondrial localization of dynamin-related protein 1 (Drp1), both of which were markedly suppressed by C60-COOH pretreatment. LPS-induced mitochondria reactive oxygen species (ROS) generation and collapse of mitochondrial membrane potential (Δ Ψm) were also significantly inhibited by C60-COOH. Moreover, we also found that C60-COOH pretreatment resulted in the attenuation of LPS-mediated activation of nuclear factor (NF)-κB and mitogen-activated protein kinase (MAPK) signaling, as well as the production of pro-inflammatory mediators. Taken together, these findings demonstrated that carboxylic acid C60 derivatives may exert neuroprotective effects through regulating mitochondrial dynamics and functions in microglial cells, thus providing novel insights into the mechanisms of the neuroprotective properties of carboxylic acid C60 derivatives.

  8. Comparison of inhibition effects of some benzoic acid derivatives on sheep heart carbonic anhydrase

    Kiliç, Deryanur; Yildiz, Melike; Şentürk, Murat; Erdoǧan, Orhan; Küfrevioǧlu, Ömer Irfan

    2016-04-01

    Carbonic anhydrase (CA) is a family of metalloenzymes that requires Zn as a cofactor and catalyze the quick conversion of CO2 to HCO3- and H+. Inhibitors of the carbonic anhydrases (CAs) have medical usage of significant diseases such as glaucoma, epilepsy, gastroduodenal ulcers, acid-base disequilibria and neurological disorders. In the present study, inhibition of CA with some benzoic derivatives (1-6) were investigated. Sheep heart CA (shCA) enzyme was isolated by means of designed affinity chromatography gel (cellulose-benzyl-sulfanylamide) 42.45-fold in a yield of 44 % with 564.65 EU/mg. Purified shCA enzyme was used in vitro studies. In the studies, IC50 values were calculated for 3-aminobenzoic acid (1), 4-aminobenzoic acid (2), 2-hydroxybenzoic acid (3), 2-benzoylbenzoic acid (4), 2,3-dimethoxybenzoic acid (5), and 3,4,5-trimethoxybenzoic acid (6), showing the inhibition effects on the purified enzyme. Such molecules can be used as pioneer for discovery of novel effective CA inhibitors for medicinal chemistry applications.

  9. Dosimetry of 64Cu-DOTA-AE105, a PET tracer for uPAR imaging

    64Cu-DOTA-AE105 is a novel positron emission tomography (PET) tracer specific to the human urokinase-type plasminogen activator receptor (uPAR). In preparation of using this tracer in humans, as a new promising method to distinguish between indolent and aggressive cancers, we have performed PET studies in mice to evaluate the in vivo biodistribution and estimate human dosimetry of 64Cu-DOTA-AE105. Methods: Five mice received iv tail injection of 64Cu-DOTA-AE105 and were PET/CT scanned 1, 4.5 and 22 h post injection. Volume-of-interest (VOI) were manually drawn on the following organs: heart, lung, liver, kidney, spleen, intestine, muscle, bone and bladder. The activity concentrations in the mentioned organs [%ID/g] were used for the dosimetry calculation. The %ID/g of each organ at 1, 4.5 and 22 h was scaled to human value based on a difference between organ and body weights. The scaled values were then exported to OLINDA software for computation of the human absorbed doses. The residence times as well as effective dose equivalent for male and female could be obtained for each organ. To validate this approach, of human projection using mouse data, five mice received iv tail injection of another 64Cu-DOTA peptide-based tracer, 64Cu-DOTA-TATE, and underwent same procedure as just described. The human dosimetry estimates were then compared with observed human dosimetry estimate recently found in a first-in-man study using 64Cu-DOTA-TATE. Results: Human estimates of 64Cu-DOTA-AE105 revealed the heart wall to receive the highest dose (0.0918 mSv/MBq) followed by the liver (0.0815 mSv/MBq), All other organs/tissue were estimated to receive doses in the range of 0.02–0.04 mSv/MBq. The mean effective whole-body dose of 64Cu-DOTA-AE105 was estimated to be 0.0317 mSv/MBq. Relatively good correlation between human predicted and observed dosimetry estimates for 64Cu-DOTA-TATE was found. Importantly, the effective whole body dose was predicted with very high precision

  10. Synthesis of some salicylic acid derivatives and studies of their interaction with uranyl ion

    Some unsubstituted and substituted bis-derivatives of salicylic acid were synthesized and their acidity constants determined spectrophotometrically in 61.10% aqueous ethanol. The stability constants of complexes which these compounds form with the UO22+ ion were determined spectrophotometrically using the method of continuous variation under the following conditions: pH 3.58 and 3.98, 61.10% aqueous ethanol, μ=0.5 (LiCl), 25±1 degC. (author). 3 figs., 2 tabs., 8 refs

  11. Use of Hydrazone Derivates as Inhibitors for the Corrosion of Nickel in Hydrochloric Acid Solution

    A.S. Fouda, H. A. Mostafa, S. E. Ghazy and S. A. El- Farah

    2007-02-01

    Full Text Available The influence of hydrazone derivatives on the corrosion of nickel in 2 mol L-1 hydrochloric acid solution has been studied using weight loss and galvanostatic polarization techniques. In general, at constant acid concentration, the inhibition efficiency increases with increasing the inhibitor concentration and decreases with increasing temperature. Polarization studies indicate that the compounds act as mixed- type inhibitors. The addition of iodide ions enhances the inhibition efficiency to a considerable extent .The effect of temperature on corrosion inhibition has been studied and activation energy has been calculated. Some thermodynamic parameters are calculated and discussed.

  12. Bioinspired bioadhesive polymers: dopa-modified poly(acrylic acid) derivatives.

    Laulicht, Bryan; Mancini, Alexis; Geman, Nathanael; Cho, Daniel; Estrellas, Kenneth; Furtado, Stacia; Hopson, Russell; Tripathi, Anubhav; Mathiowitz, Edith

    2012-11-01

    The one-step synthesis and characterization of novel bioinspired bioadhesive polymers that contain Dopa, implicated in the extremely adhesive byssal fibers of certain gastropods, is reported. The novel polymers consist of combinations of either of two polyanhydride backbones and one of three amino acids, phenylalanine, tyrosine, or Dopa, grafted as side chains. Dopa-grafted hydrophobic backbone polymers exhibit as much as 2.5 × the fracture strength and 2.8 × the tensile work of bioadhesion of a commercially available poly(acrylic acid) derivative as tested on live, excised, rat intestinal tissue. PMID:23008096

  13. Ga(III) chelates of amphiphilic DOTA-based ligands: synthetic route and in vitro and in vivo studies

    In this work, we report on a synthetic strategy using amphiphilic DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based chelators bearing a variable-sized α-alkyl chain at one of the pendant acetate arms (from 6 to 14 carbon atoms), compatible with their covalent coupling to amine-bearing biomolecules. The amphiphilic behavior of the micelles-forming Ga(III) chelates (critical micellar concentration), their stability in blood serum and their lipophilicity (logP) were investigated. Biodistribution studies with the 67Ga-labeled chelates were performed in Wistar rats, which showed a predominant liver uptake with almost no traces of the radiochelates in the body after 24 h.

  14. Ga(III) chelates of amphiphilic DOTA-based ligands: synthetic route and in vitro and in vivo studies

    Fontes, Andre [Centro de Quimica, Campus de Gualtar, Universidade do Minho, 4710-057, Braga (Portugal); Prata, M. Isabel M. [IBILI, Faculdade de Medicina, Universidade de Coimbra, 3548, Coimbra (Portugal); Geraldes, Carlos F.G.C. [Departamento de Ciencias da Vida, Faculdade de Ciencias e Tecnologia, Universidade de Coimbra, 3001-401, Coimbra (Portugal); Centro de Neurociencias e Biologia Celular, Universidade de Coimbra, 3001-401, Coimbra (Portugal); Andre, Joao P., E-mail: jandre@quimica.uminho.p [Centro de Quimica, Campus de Gualtar, Universidade do Minho, 4710-057, Braga (Portugal)

    2011-04-15

    In this work, we report on a synthetic strategy using amphiphilic DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid)-based chelators bearing a variable-sized {alpha}-alkyl chain at one of the pendant acetate arms (from 6 to 14 carbon atoms), compatible with their covalent coupling to amine-bearing biomolecules. The amphiphilic behavior of the micelles-forming Ga(III) chelates (critical micellar concentration), their stability in blood serum and their lipophilicity (logP) were investigated. Biodistribution studies with the {sup 67}Ga-labeled chelates were performed in Wistar rats, which showed a predominant liver uptake with almost no traces of the radiochelates in the body after 24 h.

  15. A Benzoic Acid Derivative and Flavokawains from Piper species as Schistosomiasis Vector Controls

    Ludmila N. Rapado

    2014-04-01

    Full Text Available The search of alternative compounds to control tropical diseases such as schistosomiasis has pointed to secondary metabolites derived from natural sources. Piper species are candidates in strategies to control the transmission of schistosomiasis due to their production of molluscicidal compounds. A new benzoic acid derivative and three flavokawains from Piper diospyrifolium, P. cumanense and P. gaudichaudianum displayed significant activities against Biomphalaria glabrata snails. Additionally, “in silico” studies were performed using docking assays and Molecular Interaction Fields to evaluate the physical-chemical differences among the compounds in order to characterize the observed activities of the test compounds against Biomphalaria glabrata snails.

  16. The First General Electron Transfer Reductions of Carboxylic Acid Derivatives Using Samarium Diiodide

    Spain, Malcolm Peter

    2014-01-01

    The development of new methods for the reduction of carboxylic acid derivatives is described. The ability to reduce these carbonyl derivatives through radical intermediates provides an orthogonal approach as compared with hydride based reductions.Initial experiments focused on the development of the SmI2–H2O system, where we have shown that chelation effects can be utilised to facilitate reduction of cyclic esters. Furthermore, a revised mechanism for the SmI2–H2O mediated reduction of lacton...

  17. Stability of Hydroxycinnamic Acid Derivatives, Flavonol Glycosides, and Anthocyanins in Black Currant Juice.

    Mäkilä, Leenamaija; Laaksonen, Oskar; Alanne, Aino-Liisa; Kortesniemi, Maaria; Kallio, Heikki; Yang, Baoru

    2016-06-01

    The stability of phenolic compounds was followed in black currant juice at ambient temperatures (in light and in dark conditions) and at +4 °C for a year. Analyses were based on high-performance liquid chromatography-diode-array detection-electrospray ionization-mass spectrometry (or tandem mass spectrometry) and high-performance liquid chromatography-diode-array detection-electrospray ionization-quadrupole time-of-flight mass spectrometry methods supported by nuclear magnetic resonance after selective high-performance liquid chromatography isolation. Altogether, 43 metabolites were identified, of which 2-(Z)-p-coumaroyloxymethylene-4-β-d-glucopyranosyloxy-2-(Z)-butenenitrile, 2-(E)-caffeoyloxymethylene-4-β-d-glucopyranosyloxy-2-(Z)-butenenitrile, 1-O-(Z)-p-coumaroyl-β-d-glucopyranose, (Z)-p-coumaric acid 4-O-β-d-glucopyranoside, and (Z)-p-coumaric acid were novel findings in black currant juice. Hydroxycinnamic acid derivatives degraded 20-40% at room temperature during one year of storage, releasing free hydroxycinnamic acids. O-Glucosides of hydroxycinnamic acid compounds were the most stable, followed by O-acylquinic acids, acyloxymethyleneglucosyloxybutenenitriles, and O-acylglucoses. Light induced the isomerization of (E)-coumaric acid compounds into corresponding Z-isomers. Flavonol glycosides stayed fairly stable. Flavonol aglycones were derived mainly from malonylglucosides. Over 90% of anthocyanins were lost at room temperature in a year, practically independent of light. Storage at low temperatures, preferably excluding light, is necessary to retain the original composition of phenolic compounds. PMID:27147482

  18. Difficult diagnosis and localization of focal nesidioblastosis: clinical implications of 68Gallium-DOTA-D-Phe1-Tyr3-octreotide PET scanning

    Kim, Jae Ri; Shin, Yong Chan; Cho, Young Min; Kim, Hongbeom; Kwon, Wooil; Han, Young Min; Kim, Sun-Whe

    2016-01-01

    Focal nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. Because it is difficult to localize and detect with current imaging modalities, nesidioblastosis is challenging for biliary-pancreatic surgeons. 68Gallium-DOTA-D-Phe1-Tyr3-octreotide PET scanning and 111indium-pentetreotide diethylene triamine pentaacetic acid octreotide scanning may be superior to conventional imaging modalities in determining the localization of nesidioblastosis. We report the successful surgical treatment of a 54-year-old woman with focal hyperplasia of the islets of Langerhans, who experienced frequent hypoglycemic symptoms and underwent various diagnostic examinations with different results. PMID:27433465

  19. Difficult diagnosis and localization of focal nesidioblastosis: clinical implications of (68)Gallium-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scanning.

    Kim, Jae Ri; Jang, Jin-Young; Shin, Yong Chan; Cho, Young Min; Kim, Hongbeom; Kwon, Wooil; Han, Young Min; Kim, Sun-Whe

    2016-07-01

    Focal nesidioblastosis is a rare cause of endogenous hyperinsulinemic hypoglycemia in adults. Because it is difficult to localize and detect with current imaging modalities, nesidioblastosis is challenging for biliary-pancreatic surgeons. (68)Gallium-DOTA-D-Phe(1)-Tyr(3)-octreotide PET scanning and (111)indium-pentetreotide diethylene triamine pentaacetic acid octreotide scanning may be superior to conventional imaging modalities in determining the localization of nesidioblastosis. We report the successful surgical treatment of a 54-year-old woman with focal hyperplasia of the islets of Langerhans, who experienced frequent hypoglycemic symptoms and underwent various diagnostic examinations with different results. PMID:27433465

  20. Gadolinium(III-DOTA Complex Functionalized with BODIPY as a Potential Bimodal Contrast Agent for MRI and Optical Imaging

    Matthias Ceulemans

    2015-11-01

    Full Text Available The synthesis and characterization of a novel gadolinium(III DOTA complex functionalized with a boron-dipyrromethene derivative (BODIPY is described. The assembly of the complex relies on azide diazotransfer chemistry in a copper tube flow reactor. The azide thus formed is coupled directly with an alkyne via click chemistry, resulting into a paramagnetic and luminescent gadolinium(III complex. Luminescent data and relaxometric properties of the complex have been evaluated, suggesting the potential applicability of the complexes as a bimodal contrast agent for magnetic resonance and optical imaging. The complex displays a bright emission at 523 nm with an absorption maximum of 507 nm and high quantum yields of up to 83% in water. The proton relaxivity of the complex measured at 310 K and at frequencies of 20 and 60 MHz had the values of 3.9 and 3.6 s−1·mM−1, respectively.

  1. Synthetic studies of coumarin derivatives from o-hydroxybenzophenones with phenylacetic acid and acetic anhydride

    Kang, Soon Hee; Yang, Sung Yun [Ewha Womans Univ., Seoul (Korea, Republic of)

    1999-02-01

    The 8 coumarin derivatives have been synthesized from 8 starting materials(2-hydroxy-benzophenone, 2,2'-dihydroxybenzophenone, 2,4-dihydroxybenzophenone, 2-hydroxy-5-methylbenzophenone, 5-chloro-2-hydroxy-4-methylbenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-methoxybenzophenone, 2-hydroxy-4-4'-dimethoxybenzophenone) with phenylacetic acid and Ac{sub 2}O/TEA in acetone at reflux temperature. The ratio of o-hydroxybenzophenone, phenylacetic acid, Ac{sub 2}O and TEA is 1:1:8:8 in acetone. Our results showed higher products yields of coumarin derivatives than Shama and Ray's method in previous papers. A new intermediate form was proposed to our mechanism of coumarin synthetic method.

  2. Lipid Peroxidation Inhibitation Activity of Maillard Reaction Products Derived from Sugar-amino Acid Model Systems

    Nanjing Zhong

    2015-08-01

    Full Text Available The present study aimed to evaluate the lipid peroxidation inhibitation activity of Maillard Reaction Products (MRPs derived from sugar (glucose, fructose, lactose and maltose and 18 amino acid model systems in soybean oil. MRPs were produced by heating at 130°C for 2 h. Of the 18 amino acids-fructose model systems studied, MRPs derived from fructose-leucine, fructose-methionine, fructose-phenylalanine and fructose-isoleucine model sytems showed high lipid peroxidation inhibitation activity and best performance was observed from fructose-phenylalanine MRPs. Interestingly, glucose-phenylalanine MRPs also exhibited high inhibitation activity and inhibitation activity of both glucose-phenylalanine and fructose-phenylalanine MRPs exceeded 87% even with concentration at 1.1 wt % after 8 days storage.

  3. N-heterocyclic Amine Derivatives as Efficient Corrosion Inhibitors for Carbon Steel in Acidic Medium

    A novel heterocyclic amine derivatives, namely N, N'-substituted pyridinyl ethylene diamine tetra acetic acid sodium salt (A) and ethylene diamine N, N'-diacetic acid di (2-methylene tetra hydro furfuryl) acetate (B) were synthesized and their structure confirmations were performed by FTIR, HNMR and CNMR spectra. The inhibition effectiveness was evaluated against the corrosion of carbon steel in 1 M HCl by weight loss and polarization techniques. The results showed that the synthesized derivatives are good corrosion inhibitors for carbon steel in 1 M HCl medium, their inhibition efficiency, increased with inhibitor concentration, and (A) is slightly more effective than (B). The potentiostatic polarization study showed that (A) and (B) are mixed-type inhibitors in 1 M HCl. These compounds prevent carbon steel from corrosion by adsorption to the steel surface and forming insoluble complexes with ferrous species. The weight loss results and potentiostatic polarization studies were in reasonable agreement. (author)

  4. Simultaneous determination of uranium(VI) and thorium(IV) with carminic acid by derivative spectrophotometry

    The reactions of uranium(VI) and thorium(IV) ions with carminic acid have been investigated. These ions react with carminic acid in neutral medium, forming colored complexes. The dark purple or red wine complexes show a high absorption in the visible region (597 nm U(VI) and 616 nm Th(IV)). Chemical variables that affect the reaction have been optimized. The spectral overlapping of the color of complexes has been resolved by first-derivative spectrophotometry. The simultaneous determination of uranium(VI) and thorium(IV) mixtures is accomplished by taking the derivative signal ('zero crossing') at 597 nm for U(VI) determination and at 616 nm for Th(IV) determination, respectively. The method has been applied to Tyuyamonite ore, containing in the matrix both ions. (author) 11 refs.; 3 figs.; 3 tabs

  5. Surface modifications of silica gel nanoparticles by silicic acid derivatives. Their structure and thermophysical properties

    The results of surface modifications of silica gel nanoparticles by silicic acid derivatives, including propyl-three-methoxy-silan (C6H16O3N), vinyl-three-(2-methoxy-ethoxy)-silan (C11H24Sl) and gamma-amino-propyl-three-methoxy-silan (C6H17O3N) were considered in this article. By means of inter esterification reaction with using silicic acid derivatives the surfaces of silica gel nanoparticles was modified. The structural changes of surface of silica gel nanoparticles after modification were evaluated by means of electron microscopy, XRD, infrared spectroscopy and differential thermal analysis methods. According to obtained results, the surface of modified samples became more hydrophobic, the water-absorbing capacity of silica gel nanoparticles decreased.

  6. Fast repair of oxidizing OH adducts of DNA by hydroxycinnamic acid derivatives. A pulse radiolytic study

    Using pulse radiolytic techniques, it has been demonstrated that the interactions of oxidizing OH adducts of DNA (ssDNA and dsDNA), polyA and polyG with hydroxycinnamic acid derivatives proceed via an electron transfer process (k=5-30x108 dm3 mol-1 s-1). In addition, the rates for fast repair of OH adducts of dAMP, polyA and DNA (ssDNA and dsDNA) are slower than the corresponding rates for the rest OH adducts of DNA constituents. The slower rates for repair of oxidizing OH adducts of dAMP may be the rate determining step during the interaction of hydroxycinnamic acid derivatives with OH adducts of DNA containing the varieties of OH adducts of DNA constituents

  7. Design and Synthesis of p/m-[p-(un)Substituted Phenylsulfonamido]phenyl β-Diketo Acids and Quinoxalone Derivatives

    ZENG,Cheng-Chu; LI,Xue-Mei; YAN,Hong; ZHONG,Ru-Gang

    2007-01-01

    Diketo acid derivatives are potent and selective HIV-1 integrase inhibitors. To investigate the detailed synthesis of those derivatives, a series of p/m-[p-(un)substituted phenylsulfonamido]phenyl β-diketo acid derivatives have been designed and synthesized. The quinoxalone derivatives as the potential bioisosteres of the biologically labile β-diketoacid pharmacophores have also been synthesized from reactions of the corresponding diketo acids with o-phenylenediamine. The structures of all diketo acid (ester) and quinoxalone derivatives were confirmed by 1H NMR, 13C NMR, IR, HRMS and/or MS (ESI). X-ray crystallographic analysis of 11b demonstrates a similar arrangement of the side chain of quinoxalone derivatives with the parent diketoacids due to the intramolecular hydrogen bond (O…H-N) and the sp2 hybridization configuration of the two nitrogen atoms of the quinoxalone ring.

  8. 68Ga-DOTA-RGD peptide: biodistribution and binding into atherosclerotic plaques in mice

    Increased expression of αvβ3/αvβ5 integrin is involved in angiogenesis and the inflammatory process in atherosclerotic plaques. The novel 68Ga-DOTA-RGD peptide binds with high affinity to αvβ3/αvβ5 integrin. The aim of this study was to investigate the uptake of the 68Ga-DOTA-RGD peptide in atherosclerotic plaques. Uptake of intravenously administered 68Ga-DOTA-RGD peptide was studied ex vivo in excised tissue samples and aortic sections of LDLR-/-ApoB100/100 atherosclerotic mice. The uptake of the tracer in aortic cryosections was examined by using digital autoradiography. Subsequently, the autoradiographs were combined with histological and immunohistological analysis of the sections. DOTA-RGD peptide was successfully labelled with the generator-produced 68Ga. The tracer had reasonably good specific radioactivity (8.7 ± 1.1 GBq/μmol) and was quite stable in vivo. According to ex vivo biodistribution results, 68Ga-DOTA-RGD was cleared rapidly from the blood circulation and excreted through the kidneys to the urine with high radioactivity in the intestine, lungs, spleen and liver. Autoradiography results showed significantly higher uptake of 68Ga-DOTA-RGD peptide in the atherosclerotic plaques compared to healthy vessel wall (mean ratio ± SD 1.4 ± 0.1, p = 0.0004). We observed that 68Ga-DOTA-RGD is accumulated into the plaques of atherosclerotic mice. However, this data only shows the feasibility of the approach, while the clinical significance still remains to be proven. Further studies are warranted to assess the uptake of this tracer into human atherosclerotic plaques. (orig.)

  9. Bioactive Compounds Derived from the Yeast Metabolism of Aromatic Amino Acids during Alcoholic Fermentation

    Albert Mas; Jose Manuel Guillamon; Maria Jesus Torija; Gemma Beltran; Cerezo, Ana B; Troncoso, Ana M.; M. Carmen Garcia-Parrilla

    2014-01-01

    Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being und...

  10. Structural Investigation for Optimization of Anthranilic Acid Derivatives as Partial FXR Agonists by in Silico Approaches

    Meimei Chen; Xuemei Yang; Xinmei Lai; Jie Kang; Huijuan Gan; Yuxing Gao

    2016-01-01

    In this paper, a three level in silico approach was applied to investigate some important structural and physicochemical aspects of a series of anthranilic acid derivatives (AAD) newly identified as potent partial farnesoid X receptor (FXR) agonists. Initially, both two and three-dimensional quantitative structure activity relationship (2D- and 3D-QSAR) studies were performed based on such AAD by a stepwise technology combined with multiple linear regression and comparative molecular field an...

  11. Local Solvent Acidities in β-Cyclodextrin Complexes with PRODAN Derivatives

    Naughton, Hannah R.; Christopher J. Abelt

    2013-01-01

    The local solvent acidities (SA scale) of six 6-carbonyl-2-aminonaphthalene derivatives as β-cyclodextrin complexes in water are determined through fluorescence quenching. The local polarities (ETN scale) are determined through the shift of the emission center-of-mass. The apparent SA values reflect the solvent structure surrounding the guest’s carbonyl group, whereas the apparent ETN values reveal the net polarity of the entire guest molecule. Comparison of these values affords greater insig...

  12. [Synthesis and properties of nuclear hydroxylated derivatives of flufenamic acid and etofenamate (author's transl)].

    Boltze, K H; Bäcker, U; Kreisfeld, H

    1982-01-01

    Synthesis of six nuclear hydroxylated derivatives of flufenamic acid and etofenamate (5-OH-, 4'-OH and 5,4'-(OH2) on a preparative scale is described. All compounds show low toxicity, but only weak anti-inflammatory activity in the rat paw kaolin edema test as compared to 2-(2-hydroxyethoxy)ethyl-N-(a,a,a-trifluoro-m-tolyl)-anthranilate (etofenamate, active substance of Rheumon Gel). PMID:7200776

  13. RNA:DNA Ratio and Other Nucleic Acid Derived Indices in Marine Ecology

    Luis Chícharo; Maria Alexandra Chícharo

    2008-01-01

    Some of most used indicators in marine ecology are nucleic acid-derived indices. They can be divided by target levels in three groups: 1) at the organism level as ecophysiologic indicators, indicators such as RNA:DNA ratios, DNA:dry weight and RNA:protein, 2) at the population level, indicators such as growth rate, starvation incidence or fisheries impact indicators, and 3) at the community level, indicators such as trophic interactions, exergy indices and prey identification. The nu...

  14. Synthesis of acrylic acid derivatives from carbon dioxide and ethylene mediated by molecular nickel complexes

    Lee, Sin Ying Tina

    2013-01-01

    This work aimed at the synthesis of acrylic acid derivatives from ethylene and CO2 and well as the investigation of β-hydride elimination reaction of nickelalactones with methyl iodide and methyl triflate to form methyl acrylate. The oxidative coupling reaction of ethylene and CO2 on nickel center was ligand selective, and gave low yields of nickelalactone product at mild synthetic conditions. Key intermediates identified and characterized in the β-H elimination reaction provided rich insight...

  15. Severe Acute Local Reactions to a Hyaluronic Acid-derived Dermal Filler

    Dyke, Susan Van; Hays, Geoffrey P.; Caglia, Anthony E.; Caglia, Michael

    2010-01-01

    Injectable fillers are normally well tolerated by patients with little or no adverse effects. The most common side effects include swelling, redness, bruising, and pain at the injection site. This report describes three cases in which patients injected with a hyaluronic acid-derived injectable filler that is premixed with lidocaine developed adverse reactions including persistent swelling, pain, and nodule formation. Two of the three patients' abscesses were cultured for aerobic and anaerobic...

  16. Coral cavity sponges depend on reef-derived food resources: stable isotope and fatty acid constraints

    van Duyl, F.C.; Moodley, L; Nieuwland, G.; IJzerloo, L. van; van Soest, R.W.M.; Houtekamer, M.; Meesters, E.H.; Middelburg, J. J.

    2011-01-01

    The diet of cavity sponges on the narrow fringing reefs of Cura double dagger ao, Caribbean was studied. The origin and resources of the bulk food of these sponges, i.e., dissolved organic matter (DOM), were identified using stable carbon and nitrogen isotopes and fatty acid biomarkers. We found that phytoplankton and its derived DOM from the adjacent open sea and from reef overlying water is not the main source of food for most of the sponges examined nor is bacterioplankton. Interestingly, ...

  17. Synthesis and Application of Phenyl Nitrone Derivatives as Acidic and Microbial Corrosion Inhibitors

    Shijun Chen; Kang Zhao; Gang Chen

    2015-01-01

    Nitrone has drawn great attention due to its wide applications as a 1,3-dipole in heterocyclic compounds synthesis and the bioactivities. With the special structure, nitrone can also be used as ligand in inorganic chemistry. Based on the current research, the nitrones are anticipated to be effective inhibitors against acidic and microbial corrosion. The aim of this work is to investigate the inhibitory action of nitrones. In this work, a series of phenyl nitrone derivatives (PN) was synthesiz...

  18. Derivatives of Salicylic Acid as Inhibitors of YopH in Yersinia pestis

    Huang, Zunnan; He, Yantao; Zhang, Xian; Gunawan, Andrea; Li WU; Zhang, Zhong-Yin; Wong, Chung F.

    2010-01-01

    Yersinia pestis causes diseases ranging from gastrointestinal syndromes to bubonic plague and could be misused as a biological weapon. As its protein tyrosine phosphatase YopH has already been demonstrated as a potential drug target, we have developed two series of forty salicylic acid derivatives and found sixteen to have micromolar inhibitory activity. We designed these ligands to have two chemical moieties connected by a flexible hydrocarbon linker to target two pockets in the active site ...

  19. Vibrational spectroscopic study of dehydroacetic acid and its cinnamoyl pyrone derivatives

    Billes, Ferenc; Elečková, Lenka; Mikosch, Hans; Andruch, Vasil

    2015-07-01

    The infrared and Raman spectra of dehydroacetic acid and some of its derivatives were measured. The assignments of the vibrational bands were based on quantum chemical calculations and normal coordinate analysis. The optimized structures, atomic net charges and dipole moments of the investigated molecules were also results of our quantum chemical calculations. The analysis of the last properties made possible a deeper insight into the structure and substituent effect on the investigated molecules. One of them is presented in the graphical abstract.

  20. Manzamenone O, new trimeric fatty acid derivative from a marine sponge Plakortis sp.

    Tanaka, Naonobu; Asai, Miki; Takahashi-Nakaguchi, Azusa; Gonoi, Tohru; Fromont, Jane; Kobayashi, Jun'ichi

    2013-05-17

    A new structurally unique trimeric fatty acid derivative, manzamenone O (1), was isolated from a marine sponge Plakortis sp. Manzamenone O (1) has a novel skeleton consisting of C-C bonded octahydroindenone and dioxabicyclo[3.3.0]octane moieties and three long aliphatic chains. The structure of 1 was elucidated on the basis of spectroscopic data and conformational analysis. Manzamenone O (1) exhibited antimicrobial activity against Micrococcus luteus, Aspergillis niger, and Trichophyton mentagrophytes. PMID:23651077

  1. Derivatives of valproic acid are active against pentetrazol-induced seizures in immature rats

    Mareš, Pavel; Kubová, Hana; Hen, N.; Yagen, B.; Bialer, M.

    2013-01-01

    Roč. 106, 1-2 (2013), s. 64-73. ISSN 0920-1211 R&D Projects: GA ČR(CZ) GAP304/10/1274; GA ČR(CZ) GBP304/12/G069 Institutional research plan: CEZ:AV0Z50110509 Institutional support: RVO:67985823 Keywords : experimental seizures * anticonvulsant action * derivatives of valproic acid * immature rats Subject RIV: FH - Neurology Impact factor: 2.190, year: 2013

  2. Aggregation behavior of cholic acid derivatives in organic solvents and in water

    Willemen, H.M.

    2002-01-01

    In this thesis various cholic acid derivatives are reported that display aggregation in water or in organic solvents. Spontaneous aggregation of single molecules into larger, ordered structures occurs at the borderline of solubility. Amphiphilic compounds, or surfactants, which possess a hydrophobic as well as a hydrophilic part, have a high tendency to form aggregates to minimize unfavorable polar-apolar interactions with the surrounding solvent. There are different types of aggregates in wa...

  3. Separation of Six Pyridoncarboylxic Acid Derivatives by Micellar and Microemulsion Electrokinetic Chromatography

    2001-01-01

    Micellar and microemulsion electrokinetic chromatography (MEKC & MEEKC) separation of six closely structural pyridoncarboylxic acid derivatives were studied and compared. Both anionic surfactant sodium dodecyl sulfate (SDS) and cationic surfactant hexadecyl-trimethyl ammonium bromide (CTAB) were used to form micellar and microemulsion as pseudostation phases, respectively. The effects of the separation conditions on retention time and selectivity were studied. Good resolutions were obtained in selected systems, indicating that there is markably different selectivity between SDS and CTAB systems.

  4. Electrochemical Biosensors Based on Ferroceneboronic Acid and Its Derivatives: A Review

    Baozhen Wang

    2014-07-01

    Full Text Available We review recent progress in the development of electrochemical biosensors based on ferroceneboronic acid (FcBA and ferrocene (Fc-modified boronic acids. These compounds can be used to construct electrochemical biosensors because they consist of a binding site (i.e., a boronic acid moiety and an electrochemically active part (i.e., an Fc residue. By taking advantage of the unique properties of FcBA and its derivatives, electrochemical sensors sensitive to sugars, glycated hemoglobin (HbA1c, fluoride (F− ions, and so forth have been widely studied. FcBA-based sugar sensors rely on the selective binding of FcBA to 1,2- or 1,3-diol residues of sugars through the formation of cyclic boronate ester bonds. The redox properties of FcBA-sugar adduct differ from those of free FcBA, which forms the basis of the electrochemical determination of sugars. Thus, non-enzymatic glucose sensors are now being actively studied using FcBA and Fc-modified boronic acids as redox markers. Using a similar principle, HbA1c can be detected by FcBA-based electrochemical systems because it contains hydrocarbon chains on the polypeptide chain. HbA1c sensors are useful for monitoring blood glucose levels over the preceding 8–12 weeks. In addition, FcBA and Fc-modified boronic acids have been used for the detection of F− ions due to the selective binding of boronic acid to F− ions. F−-ion sensors may be useful alternatives to conventional ion-selective electrodes sensitive to F− ion. Furthermore, FcBA derivatives have been studied to construct lectin; steroids; nucleotides; salicylic acid; and bacteria sensors. One of the limitations of FcBA-based sensors comes from the fact that FcBA derivatives are added in sample solutions as reagents. FcBA derivatives should be immobilized on the surface of electrodes for developing reagentless sensors.

  5. Comparison of [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate and [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotide: which peptide is preferable for PRRT?

    Esser, J.P. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands); Medisch Spectrum Twente, Department of Nuclear Medicine, Enschede (Netherlands); Krenning, E.P.; Teunissen, J.J.M.; Kooij, P.P.M.; Gameren, A.L.H. van; Bakker, W.H.; Kwekkeboom, D.J. [Erasmus MC, Department of Nuclear Medicine, Rotterdam (Netherlands)

    2006-11-15

    Patients with somatostatin receptor subtype 2-positive metastasised neuroendocrine tumours can be treated with [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate. Some use octreotide as the peptide for peptide receptor radionuclide therapy (PRRT). We compared in seven patients [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotide ({sup 177}Lu-DOTATOC) and [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-DOTATATE), to see which peptide should be preferred for PRRT with {sup 177}Lu. In the same patients, 3,700 MBq {sup 177}Lu-DOTATOC and 3,700 MBq {sup 177}Lu-DOTATATE was administered in separate therapy sessions. Amino acids were co-administered. Whole-body scanning was performed on days 1, 4 and 7 post therapy. Blood and urine samples were collected. We calculated residence times for tumours, spleen and kidneys. All patients had longer residence times in spleen, kidneys and tumours after use of {sup 177}Lu-DOTATATE (p=0.016 in each case). Comparing {sup 177}Lu-DOTATATE with {sup 177}Lu-DOTATOC, the mean residence time ratio was 2.1 for tumour, 1.5 for spleen and 1.4 for kidneys. Dose-limiting factors for PRRT are bone marrow and/or kidney dose. Although the residence time for kidneys was longer when using {sup 177}Lu-DOTATATE, the mean administered dose to tumours would still be advantageous by a factor of 1.5, assuming a fixed maximum kidney dose is reached. Plasma radioactivity after {sup 177}Lu-DOTATATE was comparable to that after {sup 177}Lu-DOTATOC. Urinary excretion of radioactivity was comparable during the first 6 h; thereafter there was a significant advantage for {sup 177}Lu-DOTATOC. {sup 177}Lu-DOTATATE had a longer tumour residence time than {sup 177}Lu-DOTATOC. Despite a longer residence time in kidneys after {sup 177}Lu-DOTATATE, tumour dose will always be higher. Therefore, we conclude that the better peptide for PRRT is octreotate. (orig.)

  6. All-trans retinoic acid promotes smooth muscle cell differentiation of rabbit bone marrow-derived mesenchymal stem cells*

    Su, Zhong-yuan; Ying LI; Zhao, Xiao-Li; Zhang, Ming

    2010-01-01

    Bone marrow-derived mesenchymal stem cells are multipotent stem cells, an attractive resource for regenerative medicine. Accumulating evidence suggests that all-trans retinoic acid plays a key role in the development and differentiation of smooth muscle cells. In the present study, we demonstrate, for the first time, that rabbit bone marrow-derived mesenchymal stem cells differentiate into smooth muscle cells upon the treatment with all-trans retinoic acid. All-trans retinoic acid increased t...

  7. [Possible ways of regulating detoxifying processes in the alcohol dehydrogenase reaction with pantothenic acid derivatives].

    Chernikevich, I P; Dorofeev, B F; Moĭseenok, A G

    1993-01-01

    Oxidation of derivatives and precursors of pantothenic acid was studied in alcohol dehydrogenase reactions. Despite the presence of free hydroxymethyl groups in a number of pantothenic acid derivatives only panthenol with Km = 8 x 10(-3) M was shown to serve as a substrate for alcohol dehydrogenase from horse liver tissue (EC 1.1.1.1) Pantethine, sodium phosphopantothenate, CoA and acetyl-CoA decreased the rate of ethanol oxidation, where pantethine and sodium phosphopantothenate were competitive inhibitors, while CoA and acetyl-CoA inhibited the enzyme noncompetitively Ki = 1.2 x 10(-2) M, 2.1 x 10(-2) M, 4.4 x 10(-4) M and 5.1 x 10(-4) M, respectively. Metabolic precursors, which were different from pantothenic acid in their structure, were not involved in the alcohol dehydrogenase reaction. Possible regulation of alcohol intoxication using derivatives and precursors of vitamin B3 is discussed. PMID:8511887

  8. Protective effects of catecholomic acid derivatives on radiation-induced damage of rat liver mitochondria

    Objective: To evaluate the effects of catecholomic acid derivatives 9501, 9502 and 7601 (CBMIDA) against radiation-induced injury of rat liver mitochondria in vitro. Methods: The injury of rat liver mitochondria was induced by γ-irradiation in vitro. The contents of MDA were assayed by spectrophotometry of TBA. The absorption value at 520 nm was measured to detect swelling of mitochondria. The electron microscopic samples of mitochondria were prepared. Results: All 9501 (5 x 10-6 mol/L), 9502(10-5 mol/L), and 7601 (10-5 mol/L) significantly inhibited radiation-induced increase of MDA information.The swelling of mitochondria induced by irradiation was also prevented by 9501, 7601. The electron micrographs also showed that 9501 markedly reduced the pathological damage of mitochondria induced by γ-irradiation. The mechanisms of anti-oxidative action of catecholomic acid derivatives was discussed. Conclusion: Injurious effect of radiation on rat liver mitochondria can be prevented by catecholomic acid derivatives 9501, 9502 and 7601 (CBMIDA)

  9. In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation

    Martinčič, Rok; Mravljak, Janez; Švajger, Urban; Perdih, Andrej; Anderluh, Marko; Novič, Marjana

    2015-01-01

    A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which ...

  10. Quantitative structure-activity relationships of antimicrobial fatty acids and derivatives against Staphylococcus aureus

    Hui ZHANG; Lu ZHANG; Li-juan PENG; Xiao-wu DONG; Di WU; Vivian Chi-Hua WU; Feng-qin FENG

    2012-01-01

    Fatty acids and derivatives (FADs) are resources for natural antimicrobials.In order to screen for additional potent antimicrobial agents,the antimicrobial activities of FADs against Staphylococcus aureus were examined using a microplate assay.Monoglycerides of fatty acids were the most potent class of fatty acids,among which monotridecanoin possessed the most potent antimicrobial activity.The conventional quantitative structure-activity relationship (QSAR) and comparative molecular field analysis (CoMFA) were performed to establish two statistically reliable models (conventional QSAR:R2=0.942,Q2LOO=0.910; CoMFA:R2=0.979,Q2=0.588,respectively).Improved forecasting can be achieved by the combination of these two models that provide a good insight into the structureactivity relationships of the FADs and that may be useful to design new FADs as antimicrobial agents.

  11. Hybrid Compounds Strategy in the Synthesis of Oleanolic Acid Skeleton-NSAID Derivatives

    Anna Pawełczyk

    2016-04-01

    Full Text Available The current study focuses on the synthesis of several hybrid individuals combining a natural oleanolic acid skeleton and synthetic nonsteroidal anti-inflammatory drug moieties (NSAIDs. It studied structural modifications of the oleanolic acid structure by use of the direct reactivity of hydroxyl or hydroxyimino groups at position C-3 of the triterpenoid skeleton with the carboxylic function of anti-inflammatory drugs leading to new perspective compounds with high potential pharmacological activities. Novel ester- and iminoester-type derivatives of oleanolic unit with the different NSAIDs, such as ibuprofen, aspirin, naproxen, and ketoprofen, were obtained and characterized. Moreover, preliminary research of compounds obtaining structure stability under acidic conditions was examined and the PASS method of prediction of activity spectra for substances was used to estimate the potential biological activity of these compounds.

  12. Hybrid Compounds Strategy in the Synthesis of Oleanolic Acid Skeleton-NSAID Derivatives.

    Pawełczyk, Anna; Olender, Dorota; Sowa-Kasprzak, Katarzyna; Zaprutko, Lucjusz

    2016-01-01

    The current study focuses on the synthesis of several hybrid individuals combining a natural oleanolic acid skeleton and synthetic nonsteroidal anti-inflammatory drug moieties (NSAIDs). It studied structural modifications of the oleanolic acid structure by use of the direct reactivity of hydroxyl or hydroxyimino groups at position C-3 of the triterpenoid skeleton with the carboxylic function of anti-inflammatory drugs leading to new perspective compounds with high potential pharmacological activities. Novel ester- and iminoester-type derivatives of oleanolic unit with the different NSAIDs, such as ibuprofen, aspirin, naproxen, and ketoprofen, were obtained and characterized. Moreover, preliminary research of compounds obtaining structure stability under acidic conditions was examined and the PASS method of prediction of activity spectra for substances was used to estimate the potential biological activity of these compounds. PMID:27077841

  13. Gel electrophoresis study of radioprotective effect of hydroxy cinnamic acid derivatives on DNA

    The radioprotective effect exerted by hydroxy cinnamic acid derivatives on the radiation damage of DNA, such as double-strand break (DSB) and intermolecular crosslinking (CL), has been studied by gel electrophoresis. The molecular length distribution of DNA can be measured by this method, and by comparing average molecular length of DNA before and after irradiation, the frequency of DSB and CL can be determined quantitatively. The radioprotective effect of caffeic acid and sinapine on calf thymus DNA in binary system at room temperature have been determined. Both caffeic acid and sinapine reveal apparent protective effects and the former is stronger than the latter. The mechanism of radioprotection at room temperature has been discussed. Based on this finding, combined with the previous ESR study and an analysis of the molecular structure on these two protectors, it is suggested that the target is protected as a result of hydrogen atom transfering from protector to target

  14. Naturally occurring amino acid derivatives with herbicidal, fungicidal or insecticidal activity.

    Lamberth, Clemens

    2016-04-01

    Several naturally occurring amino acid derivatives display significant activities against weeds, fungi and insects: some of them have been even commercialized and are applied as crop protection agents. The 53 most important amino acid natural products with such efficacy are presented in this review together with their natural source, mode of action and biological activity. The diversity of the manifold bacterial, fungal and plantal sources of these compounds is impressive as well as their completely different structural scaffolds, ranging from cyclopeptides via unique non-proteinogenic amino acids to peptidyl nucleosides, the broad range of target enzymes from several different biochemical pathways, which they inhibit and also the plethora of different weeds, fungi and insects they are able to control. PMID:26801938

  15. Synthesis and screening of ursolic acid-benzylidine derivatives as potential anti-cancer agents.

    Dar, Bilal Ahmad; Lone, Ali Mohd; Shah, Wajaht Amin; Qurishi, Mushtaq Ahmad

    2016-03-23

    Ursolic acid present abundantly in plant kingdom is a well-known compound with various promising biological activities including, anti-cancer, anti-inflammatory, hepatoprotective, antiallergic and anti-HIV properties. Herein, a library of ursolic acid-benzylidine derivatives have been designed and synthesized using Claisen Schmidt condensation of ursolic acid with various aromatic aldehydes in an attempt to develop potent antitumor agents. The compounds were evaluated against a panel of four human carcinoma cell lines including, A-549 (lung), MCF-7 (breast), HCT-116 (colon), THP-1 (leukemia) and a normal human epithelial cell line (FR-2). The results from MTT assay revealed that all the compounds displayed high level of antitumor activities compared with the triazole analogs (previously reported) and the parent ursolic acid. However, compound 3b, the most active derivative was subjected to mechanistic studies to understand the underlying mechanism. The results revealed that compound 3b induced apoptosis in HCT-116 cell lines, arrest cell cycle in the G1 phase, caused accumulation of cytochrome c in the cytosol and increased the expression levels of caspase-9 and caspase-3 proteins. Therefore, compound 3b induces apoptosis in HCT-116 cells through mitochondrial pathway. PMID:26854375

  16. Simultaneous analysis of ellagic acid and coenzyme Q(10) by derivative spectroscopy and HPLC.

    Ratnam, D Venkat; Bhardwaj, V; Kumar, M N V Ravi

    2006-09-15

    Antioxidants are gaining tremendous interest as chemopreventive as well as chemotherapeutic agents. Ellagic acid (EA) is a plant derived compound with very poor solubility in water and very low octanol/water partition coefficient and coenzyme Q(10) (CoQ(10)) is a highly lipophilic compound, which is synthesized in the body and can be derived from food supplements as well. The new insights in the combination therapy are promising a better future in many challenging diseases. Synergism is among the key advantages of combination therapy apart from decreased intensity of unwanted effects of a compound, increased patient compliance and reduction in cost of therapy. EA and CoQ(10) supplementation in combination will be beneficial in strengthening the weakened antioxidant defense system in many diseases related to oxidative stress. Here we report first derivative UV spectroscopic and HPLC methods for the simultaneous analysis of these two agents in pharmaceutical preparations. Results obtained indicate that the derivative spectroscopy is as efficient as HPLC method in quantitative analysis. Retention of ellagic acid can be increased using PEG bonded column which is poorly retained on C(18) column. PEG column can be used for rapid simultaneous analysis of EA and CoQ(10), which are having diverse physicochemical properties. PMID:18970780

  17. The effect of short-chain fatty acids on human monocyte-derived dendritic cells

    Nastasi, Claudia; Candela, Marco; Bonefeld, Charlotte Menné;

    2015-01-01

    negligible effects, while both butyrate and propionate strongly modulated gene expression in both immature and mature human monocyte-derived DC. An Ingenuity pathway analysis based on the differentially expressed genes suggested that propionate and butyrate modulate leukocyte trafficking, as SCFA strongly......The gut microbiota is essential for human health and plays an important role in the pathogenesis of several diseases. Short-chain fatty acids (SCFA), such as acetate, butyrate and propionate, are end-products of microbial fermentation of macronutrients that distribute systemically via the blood....... The aim of this study was to investigate the transcriptional response of immature and LPS-matured human monocyte-derived DC to SCFA. Our data revealed distinct effects exerted by each individual SCFA on gene expression in human monocyte-derived DC, especially in the mature ones. Acetate only exerted...

  18. Preparation and structural characterisation of novel and versatile amphiphilic octenyl succinic anhydride-modified hyaluronic acid derivatives

    Eenschooten, Corinne Diane; Guillaumie, Fanny; Kontogeorgis, Georgios;

    2010-01-01

    The purpose of the present study was to prepare amphiphilic hyaluronic acid (HA) derivatives and to study the influence of a selection of reaction parameters on the degree of substitution (DS) of the derivatives. Octenyl succinic anhydride (OSA)–modified HA (OSA–HA) derivatives were prepared and...

  19. Ring-extended derivatives of gramicidin S with furanoid sugar amino acids in the turn region have enhanced antimicrobial activity

    Knijnenburg, A.D.; Spalburg, E.; Neeling, A.J. de; Mars-Groenendijk, R.H.; Noort, D.; Grotenbreg, G.M.; Marel, G.A. van der; Overkleeft, H.S.; Overhand, M.

    2009-01-01

    (Chemical Equation Presented) A series of ring-extended gramicidin S (GS) derivatives containing furanoid sugar amino acids were evaluated. Although the extended GS derivatives have a less well-defined secondary structure as determined by NMR and CD, some derivatives show an improved biological prof

  20. Electrochemical and optical sugar sensors based on phenylboronic acid and its derivatives

    Egawa, Yuya; Seki, Toshinobu [Faculty of Pharmaceutical Sciences, Josai University, Keyakidai, Sakado, Saitama 350-0295 (Japan); Takahashi, Shigehiro [Graduate School of Pharmaceutical Sciecnes, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578 (Japan); Anzai, Jun-ichi, E-mail: junanzai@mail.pharm.tohoku.ac.jp [Graduate School of Pharmaceutical Sciecnes, Tohoku University, Aramaki, Aoba-ku, Sendai 980-8578 (Japan)

    2011-10-10

    Recent progress in electrochemical and optical sugar sensors based on phenylboronic acid (PBA) and its derivatives as recognition components is reviewed. PBAs are known to bind diol compounds including sugars to form cyclic boronate esters that are negatively charged as a result of the addition of OH{sup -} ions from solution. Based on the formation of PBA charged species, sugars and their derivatives can be detected by means of electrochemical and optical techniques. For the development of PBA-based electrochemical sensing systems or sensors, PBA is modified with a redox-active marker, because PBA itself is electrochemically inactive, and ferrocene derivatives are often employed for this purpose. Ferrocene-modified PBAs have been used as redox-active additives in solution for the electrochemical detection of sugars and derivatives. PBA-modified electrodes have also been constructed as reagentless electrochemical sensors, where PBAs are immobilized on the surface of metal and carbon electrodes through mainly two routes: as a self-assembled monolayer film and as a polymer thin film. PBA-modified electrodes can be successfully used to detect sugars and derivatives through potentiometric and voltammetric responses. In addition, PBA-modified electrodes can be used for the immobilization of glycoenzymes on an electrode surface by the formation of boronate esters with carbohydrate chains in the glycoenzymes, thus resulting in enzyme biosensors. For the development of PBA-based optical sensors, a variety of chromophores and fluorophores have been coupled with PBA. Azobenzene dyes have been most frequently used for the preparation of colorimetric sugar sensors, in which the absorption wavelength and intensity of the dye are dependent on the type and concentration of added sugars. The sensitivity of the sensors is significantly improved based on multi-component systems in which alizalin red S, pyrocatechol violet, starch-iodine complex, and cyclodextrin are employed as

  1. Electrochemical and optical sugar sensors based on phenylboronic acid and its derivatives

    Recent progress in electrochemical and optical sugar sensors based on phenylboronic acid (PBA) and its derivatives as recognition components is reviewed. PBAs are known to bind diol compounds including sugars to form cyclic boronate esters that are negatively charged as a result of the addition of OH- ions from solution. Based on the formation of PBA charged species, sugars and their derivatives can be detected by means of electrochemical and optical techniques. For the development of PBA-based electrochemical sensing systems or sensors, PBA is modified with a redox-active marker, because PBA itself is electrochemically inactive, and ferrocene derivatives are often employed for this purpose. Ferrocene-modified PBAs have been used as redox-active additives in solution for the electrochemical detection of sugars and derivatives. PBA-modified electrodes have also been constructed as reagentless electrochemical sensors, where PBAs are immobilized on the surface of metal and carbon electrodes through mainly two routes: as a self-assembled monolayer film and as a polymer thin film. PBA-modified electrodes can be successfully used to detect sugars and derivatives through potentiometric and voltammetric responses. In addition, PBA-modified electrodes can be used for the immobilization of glycoenzymes on an electrode surface by the formation of boronate esters with carbohydrate chains in the glycoenzymes, thus resulting in enzyme biosensors. For the development of PBA-based optical sensors, a variety of chromophores and fluorophores have been coupled with PBA. Azobenzene dyes have been most frequently used for the preparation of colorimetric sugar sensors, in which the absorption wavelength and intensity of the dye are dependent on the type and concentration of added sugars. The sensitivity of the sensors is significantly improved based on multi-component systems in which alizalin red S, pyrocatechol violet, starch-iodine complex, and cyclodextrin are employed as indicators

  2. 68Ga-DOTA0-Tyr3-octreotide positron emission tomography in nasopharyngeal carcinoma

    PET/CT with 68Ga-labelled [DOTA0,Tyr3]-octreotide (68Ga-DOTA-TOC PET/CT) is a routinely used imaging modality for neuroendocrine tumours expressing somatostatin receptors (SSTR). Recent studies have shown SSTR expression in head and neck squamous cell carcinoma, albeit lower than in highly differentiated neuroendocrine tumours. We sought to determine whether nasopharyngeal carcinoma (NPC) positive for Epstein-Barr virus (EBV), a rare subtype of head and neck cancer, shows increased 68Ga-DOTA-TOC uptake indicating expression of SSTR. Five patients with untreated, histologically proven EBV-positive NPC were referred for 68Ga-DOTA-TOC PET/CT. Tracer uptake in tumour lesions was assessed visually and semiquantitatively measuring maximum standardized uptake values (SUVmax) and tumour to background ratios. Increased tumour-specific uptake was detected in all five patients with a median SUVmax of 10.6 (range 3.6 - 17.1) in the primary tumour and 13.2 (range 6.1 - 14.5) in cervical lymph node metastases. 68Ga-DOTA-TOC PET/CT demonstrated tracer uptake in EBV-positive NPC comparable to that in highly differentiated neuroendocrine tumours. This observation is consistent with increased SSTR expression in EBV-positive NPC and may open new diagnostic and therapeutic windows in NPC. (orig.)

  3. Gd-DOTA enhancement of cerebral and spinal tumors on MR imaging

    The use of Gd-DOTA as a contrast agent in MR imaging to improve the diagnosis of cerebral and spinal tumors was assessed in 20 patients, ten with brain tumors and ten with spinal tumors. Imaging was performed with a 0.5-T Magniscan 5000 unit. T1-weighted (spin-echo and gradient-echo) and T2-weighted (spin-echo) images were acquired before and after intravenous injection of Gd-DOTA, 0.1 mmol/kg. On T1-weighted images, Gd-DOTA enhanced sites of presumed disruption of the blood-brain barrier. This made some brain tumors more conspicuous and helped target biopsies, but did not reveal any additional lesions. On the other hand, the use of Gd-DOTA significantly improved the reliability of spinal tumor imaging compared to imaging performed without contrast agent, allowing delineation of abnormalities on T1-weighted images, which frequently contain fewer artifacts than the most sensitive T2-weighted images. Images obtained with Gd-DOTA could be used by the physician to rule out residual tumor after surgery and to assess recurrences. Additional work should be done to discover whether spinal tumor exploration with MR imaging could include solely T1-weighted sequences, performed before and after contrast agent administration, without T2-weighted sequences

  4. Use of humic acids derived from peat and lignite as phenanthrene sorbents

    Sofikitis, Elias; Giannouli, Andriana; Kalaitzidis, Stavros; Christanis, Kimon; Karapanagioti, Hrissi K.; Papanicolaou, Cassiani

    2015-04-01

    A broad range of materials is being applied for environmental remediation of water, among them sorbents such as humic acids. Being natural substances, the extraction and purification of humic acids might be cheaper than the production of synthetic sorbents. Having higher absorbing capacity than most of the sorbents used to date, humic acids have a competitive advantage against commonly used sorbents such as active charcoals and biochar. Humic acids are "complex colloidal super-mixtures" that are characterized by their functional groups. Therefore, composition and molecular formula can vary depending on the properties of the parent material. The aim of this project was (a) to study the sorption capacity of humic acids derived from peat and lignite samples picked up from deposits spread throughout Greece and (b) to compare the results with these of the parent materials. This comparison provides an insight to which matrix samples are suitable for further chemical treatment for the isolation of humic acids to be used as sorbents. The selected model pollutant was phenanthrene, which is a PAH that consists of three fused benzene rings. Humic acids were extracted according to the methodology proposed by the IHSS, slightly modified, in order to fit better to the properties of organic sediments. Sorption experiments were conducted by mixing 0.004 g of the sorbent (peat or lignite or humic acid) with aqueous solutions of phenanthrene at different concentrations of 30, 50, 100, 300, and 500 μg/L. The results show that phenanthrene sorption is higher for the humic acid than for the original lignite and peat samples. The original samples display higher sorption at the lower phenanthere solutions (30 μg/L; Kd ranges from 15,000 to 47,000 L/kg) than at the higher one (500 μg/L; Kd ranges from 4,100 to 13,000 L/Kg) suggesting non-linear sorption. The humic acids display mainly linear isotherms with Kd ranges from 6,600 to 120,000 L/kg. Concerning the suitability of the studied

  5. Antiproliferative and cytotoxic profiles of antipsoriatic fumaric acid derivatives in keratinocyte cultures.

    Sebök, B; Bonnekoh, B; Geisel, J; Mahrle, G

    1994-01-01

    Oral administration with complex mixtures of fumaric acid derivatives is known to have antipsoriatic efficacy. The present studies aimed to clarify the mode of action and toxicity of the individual compounds. Hyperproliferative HaCaT keratinocytes in monolayer cultures were exposed to fumaric acid, dimethylfumarate, zinc monoethylfumarate, calcium monoethylfumarate and magnesium monoethylfumarate at concentrations between 0.4 microM and 960 microM for 48 h. Cell proliferation was studied by [3H]thymidine incorporation. In addition 14C-labelled amino acid uptake and total protein content were measured. Direct cytotoxicity was determined by the release of cytoplasmic lactate dehydrogenase (LDH) into the culture medium. The corresponding 50% inhibition concentrations (IC50) were calculated for DNA/protein synthesis: 2.3/2.5 microM (dimethylfumarate), 133/145 microM (zinc monoethylfumarate), 215/230 microM (calcium monoethylfumarate), 275/270 microM (magnesium monoethylfumarate), > 960/> 960 microM (fumaric acid). The total protein content was less sensitive. Antiproliferative activity was found for dimethylfumarate and to a lesser degree for calcium monoethylfumarate already at the subtoxic concentrations of 1.3 and 4 microM, respectively. In the case of magnesium monoethylfumarate, zinc monoethylfumarate and fumaric acid there was no such dissociation between their cytotoxic and antiproliferative potential. These data indicate that most of the antipsoriatic potential of fumaric therapies is due to the dimethylfumarate compound. PMID:8157084

  6. Production of chlorogenic acid and its derivatives in hairy root cultures of Stevia rebaudiana.

    Fu, Xiao; Yin, Zhong-Ping; Chen, Ji-Guang; Shangguan, Xin-Chen; Wang, Xiaoqiang; Zhang, Qing-Feng; Peng, Da-Yong

    2015-01-14

    Chlorogenic acid and its derivatives (CADs) are valuable bioactive plant secondary metabolites with many health benefits. In the present study, Stevia rebaudiana hairy root cultures were established, and the culture conditions for the production of CADs were optimized. The hairy roots were induced by coculture of S. rebaudiana leaves and Agrobacterium rhizogenes (C58C1) after infection, which were further verified by PCR detection of rolB and rolC genes. HPLC-MS and HPLC analysis showed that chlorogenic acid (3-caffeoylquinic acid, 3-CQA), 3,5-dicaffeoylquinic acid (3,5-CQA), and 4,5-dicaffeoylquinic acid (4,5-CQA) were the major CADs in the hairy roots. Eight single roots with rapid growth rate were selected. Among them, T3 had the highest yield of CADs. B5 medium supplemented with 40 g/L sucrose was more suitable for the production of CADs than others. Under optimal culture conditions, the total content of these three compounds reached 105.58 mg/g and total yield was 234.40 mg/100 mL. PMID:25548875

  7. Chirality of meteoritic free and IOM-derived monocarboxylic acids and implications for prebiotic organic synthesis

    Aponte, José C.; Tarozo, Rafael; Alexandre, Marcelo R.; Alexander, Conel M. O.'D.; Charnley, Steven B.; Hallmann, Christian; Summons, Roger E.; Huang, Yongsong

    2014-04-01

    The origin of homochirality and its role in the development of life on Earth are among the most intriguing questions in science. It has been suggested that carbonaceous chondrites seeded primitive Earth with the initial organic compounds necessary for the origin of life. One of the strongest pieces of evidence supporting this theory is that certain amino acids in carbonaceous chondrites display a significant L-enantiomeric excess (ee), similar to those use by terrestrial life. Analyses of ee in meteoritic molecules other than amino acids would shed more light on the origins of homochirality. In this study we investigated the stereochemistry of two groups of compounds: (1) free monocarboxylic acids (MCAs) from CM2 meteorites LON 94101 and Murchison; and (2) the aliphatic side chains present in the insoluble organic matter (IOM) and extracted in the form of monocarboxylic acids (MCAs) from EET 87770 (CR2) and Orgueil (CI1). Contrary to the well-known ee observed for amino acids in meteorites, we found that meteoritic branched free and IOM-derived MCAs with 5-8 carbon atoms are essentially racemic. The racemic nature of these compounds is used to discuss the possible influence of ultraviolet circularly polarized light (UVCPL) and aqueous alterations on the parent body on chirality observed in in carbonaceous chondrites.

  8. Metallic Langmuir and Langmuir-Blodgett films based on TTF derivatives and fatty acid

    Recent progress in the metallic conducting Langmuir-Blodgett (LB) films built from TTF derivative and fatty acids is reported. A simple LB method of transferring the mixed Langmuir (L) film of BEDO-TTF (BO) and stearic acid (SA) onto substrates provided metallic conducting LB films. A homogeneous L film formation on the water surface observed by Brewster angle microscope (BAM) is an essential factor for the well-ordered LB films. In the L film, the carboxylate group of fatty acid forms anion layer bringing about a spontaneous formation of mixed valence state (MVS) of BO layer. Similar spontaneous formation was also found in the molecular combination of nonoxygen-substituted donor of EDT-TTF and octadecanesulfonic acid (OS). This type of reaction would be useful for obtaining conducting LB films. For the LB films of BEDO-TTF and stearic acid, we found a negative transverse magnetoresistance at low temperature that was interpreted in the weak localization of a two-dimensional (2D) electronic system based on the well-defined conducting layer

  9. Natural derivatives of diphenolic acid as substitutes for bisphenol-A

    Ertl, Johanna; Cerri, Elisa; Rizzuto, Matteo; Caretti, Daniele

    2014-05-01

    Diphenolic acid had been originally used in the first epoxy resins and was later on forgotten as it was substituted by the cheaper bisphenol A. But in the recent years major health concerns have been raised as bisphenol A has a pseudo-hormonal effect on the body, playing the role of estrogen it can cause a severe impact on the organism, especially in males. Moreover it is produced from acetone and phenol, both from fossil, and thus limited resources. On the contrary, diphenolic acid is synthesized from levulinic acid and phenol. Levulinic acid being directly produced by hydrolysis of biomass. By substituting the fossil phenol with natural phenols from lignin or plant extraction we are able to synthesize a fully renewable substitute for bisphenol A. The reactions to yield an epoxy resin have been examined and the reactivity with epichlorohydrin is satisfying. Moreover, some of the derivatives of diphenolic acid have interesting curing properties and preliminary results show excellent properties of the cured resin, including thermal stability and pencil hardness.

  10. Formation and Characterization of Self-Assembled Phenylboronic Acid Derivative Monolayers toward Developing Monosaccaride Sensing-Interface

    Kwangnak Koh

    2007-08-01

    Full Text Available We designed and synthesized phenylboronic acid as a molecular recognitionmodel system for saccharide detection. The phenylboronic acid derivatives that haveboronic acid moiety are well known to interact with saccharides in aqueous solution; thus,they can be applied to a functional interface of saccharide sensing through the formation ofself-assembled monolayer (SAM. In this study, self-assembled phenylboronic acidderivative monolayers were formed on Au surface and carefully characterized by atomicforce microscopy (AFM, Fourier transform infrared reflection absorption spectroscopy(FTIR-RAS, surface enhanced Raman spectroscopy (SERS, and surface electrochemicalmeasurements. The saccharide sensing application was investigated using surface plasmonresonance (SPR spectroscopy. The phenylboronic acid monolayers showed goodsensitivity of monosaccharide sensing even at the low concentration range (1.0 × 10-12 M.The SPR angle shift derived from interaction between phenylboronic acid andmonosaccharide was increased with increasing the alkyl spacer length of synthesizedphenylboronic acid derivatives.

  11. Characteristics of Hyaluronic Acid Derivative Cross-linked by Polyethylene Glycol

    2005-01-01

    Characteristic and dynamic viscosities of Hyaluronic acid ( HA ) derivative modified by polyethylene glycol (PEG) were tested with different reaction times (6 h,12 h,18 h and 24 h ) , different molar ratio of HA/PEG ( 1/10,1/5,1/3 and 1/2), different molecular weight of PEG(400,6 000 and 20 000) and mass fraction is 0.4% by Wushi Viscosimeter and L- 90 Rheometer at 25 ℃. Characteristic viscosity of HA derivative had the largest value in 12 h, which decreased with increasing of PEG molecular weight, but its aqueous dynamic viscosity increased with increment of PEG molecular weight. Meanwhile, we tested dynamic mechanic properties of HA derivative by 3ARES3 Rheometer at 25 ℃ to study viscoelastic changes and to compare change difference from viscosity to elasticity with the changes of vibration frequency between unmodified HA and HA derivative.Change from low vibrated frequency to high one of solution resulted in change from viscosity to elasticity of solution. In conclusion, as to the rheological properties, structure-modified HA derivative meets the requirement of biomnterial .

  12. Catalytic Kinetic Determination of Micro Amounts of Oxalic Acid by Second-Order Derivative Oscillopolarography

    2001-01-01

    It was found that micro amounts of oxalate showed a very strong catalytic effect on the slow reaction between K2Cr2O7 and Orange Ⅳ in a diluted sulfuric acid medium in a water bath at 70 ℃. Orange Ⅳ exhibited a sensitive second-order derivative polarographic wave at -0.50 V(vs. SCE). This provides the basis for a sensitive and selective catalytic kinetic method for oxalate determination with second-order derivative oscillopolarography. The effects of sulphuric acid, K2Cr2O7, and orange Ⅳ concentrations, reaction temperature and reaction time were investigated. A calibration curve of oxalate in the range of 0.1—2.0 μg/mL was obtained by the fixed-time procedure. The detection limit was 0.03 μg/ mL. The possible interference from co-existing substances or ions was examined. The new method has a high sensitivity and a good selectivity compared to other existing methods for oxalic acid determination. It has been applied to the determination of micro amounts of oxalate in real urine samples with satisfactory results.

  13. Production of fatty acid-derived oleochemicals and biofuels by synthetic yeast cell factories.

    Zhou, Yongjin J; Buijs, Nicolaas A; Zhu, Zhiwei; Qin, Jiufu; Siewers, Verena; Nielsen, Jens

    2016-01-01

    Sustainable production of oleochemicals requires establishment of cell factory platform strains. The yeast Saccharomyces cerevisiae is an attractive cell factory as new strains can be rapidly implemented into existing infrastructures such as bioethanol production plants. Here we show high-level production of free fatty acids (FFAs) in a yeast cell factory, and the production of alkanes and fatty alcohols from its descendants. The engineered strain produces up to 10.4 g l(-1) of FFAs, which is the highest reported titre to date. Furthermore, through screening of specific pathway enzymes, endogenous alcohol dehydrogenases and aldehyde reductases, we reconstruct efficient pathways for conversion of fatty acids to alkanes (0.8 mg l(-1)) and fatty alcohols (1.5 g l(-1)), to our knowledge the highest titres reported in S. cerevisiae. This should facilitate the construction of yeast cell factories for production of fatty acids derived products and even aldehyde-derived chemicals of high value. PMID:27222209

  14. [Antithrombotic therapy after myocardial infarction: arguments for the use of acetylsalicylic acid and coumarin derivatives].

    Waskowsky, W M; Brouwer, A; Verheugt, F W A

    2005-01-01

    Patients who survived myocardial infarction and who are being treated with the current optimal therapy (antithrombotics, statins and beta-blockers), have a 10-20% chance of death, re-infarction and stroke within in the first year. A possible explanation for this could be an increased activation and generation ofthrombin for at least 6 months following the cardiovascular event preceding preventative therapy. Acetylsalicylic acid and clopidogrel do not affect activation by thrombin of the platelet aggregation and the clotting cascade. The additional use of cumarin derivatives could therefore reduce the chance of recurring thrombotic events, and subsequently improve prognosis. Since the nineteen-nineties several randomised trials have been conducted to study the clinical relevance ofcumarin derivatives both with and without acetylsalicylic acid, in patients who had had a myocardial infarction. The conclusions of these studies were not unambiguous. If the international normalized ratio (INR) was kept > 2 for a long period, by means of frequent check-ups and effective dosage adjustment, the chance of death, recurrent myocardial infarction or stroke was 30-50% lower than when acetylsalicylic acid only was used. The risk of bleeding was raised by 2-4 times, but there were no life-threatening episodes of bleeding. In view of the recent development of anticoagulant agents, for which monitoring seems to be becoming unnecessary, identification of patients who would benefit most from a combined antithrombotic strategy is warranted. PMID:15688836

  15. Uptake kinetics of the somatostatin receptor ligand [86Y]DOTA-dPhe1-Tyr3-octreotide ([86Y]SMT487) using positron emission tomography in non-human primates and calculation of radiation doses of the 90Y-labelled analogue

    [90Y]DOTA-dPhe1-Tyr3-octreotide ([90Y]-SMT487) has been suggested as a promising radiotherapeutic agent for somatostatin receptor-expressing tumours. In order to quantify the in vivo parameters of this compound and the radiation doses delivered to healthy organs, the analogue [86Y]DOTA-dPhe1-Tyr3-octreotide was synthesised and its uptake measured in baboons using positron emission tomography (PET). [86Y]DOTA-dPhe1-Tyr3-octreotide was administered at two different peptide concentrations, namely 2 and 100 μg peptide per m2 body surface. The latter concentration corresponded to a radiotherapeutic dose. In a third protocol [86Y]DOTA-dPhe1-Tyr3-octreotide was injected in conjunction with a simultaneous infusion of an amino acid solution that was high in l-lysine in order to lower the renal uptake of radioyttrium. Quantitative whole-body PET scans were recorded to measure the uptake kinetics for kidneys, liver, lung and bone. The individual absolute uptake kinetics were used to calculate the radiation doses for [90Y]DOTA-dPhe1-Tyr3-octreotide according to the MIRD recommendations extrapolated to a 70-kg human. The highest radiation dose was received by the kidneys, with 2.1-3.3 mGy per MBq [90Y]DOTA-dPhe1-Tyr3-octreotide injected. For the 100 μg/m2 SMT487 protocol with amino acid co-infusion this dose was about 20%-40% lower than for the other two treatment protocols. The liver and the red bone marrow received doses ranging from 0.32 to 0.53 mGy and 0.03 to 0.07 mGy per MBq [90Y]DOTA-dPhe1-Tyr3-octreotide, respectively. The average effective dose equivalent amounted to 0.23-0.32 mSv/MBq. The comparatively low estimated radiation doses to normal organs support the initiation of clinical phase I trials with [90Y]DOTA-dPhe1-Tyr3-octreotide in patients with somatostatin receptor-expressing tumours. (orig.)

  16. High specificity in response of the sodium-dependent multivitamin transporter to derivatives of pantothenic acid.

    Chirapu, Srinivas Reddy; Rotter, Charles J; Miller, Emily L; Varma, Manthena V; Dow, Robert L; Finn, M G

    2013-01-01

    Essential nutrients are attractive targets for the transport of biologically active agents across cell membranes, since many are substrates for active cellular importation pathways. The sodium-dependent multivitamin transporter (SMVT) is among the best characterized of these, and biotin derivatives have been its most popular targets. We have surveyed 45 derivatives of pantothenic acid, another substrate of SMVT, long known as a competitive inhibitor of biotin transport. Variations of the β-alanyl fragment of pantothenate were uniformly rejected by the transporter, including derivatives with very similar steric and acidic characteristics to the natural substrate. The secondary hydroxyl of the 2,2-dimethyl-1,3-propanediol (pantoyl) fragment was the only position at which potential linkers could be attached while retaining activity as an inhibitor of biotin uptake and a substrate for sodium-dependent transport. However, triazole conjugates to several drug-like cargo motifs were not accepted as substrates by human SMVT in cell culture. Two compounds were observed which did not inhibit biotin uptake but were themselves transported in a sodium-dependent fashion, suggesting more complex behavior than expected. These studies represent the most extensive examination to date of pantothenate as an anchor for SMVT-mediated drug delivery, showing that this route requires further investigation before being judged promising. PMID:23578027

  17. Nutritional stability of various naturally occurring monoglutamate derivatives of folic acid.

    O'Broin, J D; Temperley, I J; Brown, J P; Scott, J M

    1975-05-01

    The nutritional stabilities of four major dietary folates were studied as their corresponding monoglutamates and were compared to pteroylglutamate (folic acid) itself. The study of the monoglutamyl rather than polyglutamyl forms was justified since the former are formed during the course of digestion and also addition of extra glutamyl residues is unlikely to affect the types of nutritional instability associated with these derivatives. Since ability to support growth in Lactobacillus casei is known to reflect nutritional activity in man this organism was used in the stability studies. It was found that pteroylglutamate and 5-formyltetrahydropteroylglutamate had nutritional stabilities of the order of weeks although the stability of the former was decreased by phosphate. Surprisingly 10-formyltetrahydropteroylglutamate was nutritionally more stable than expected, possibly due to its conversion to the more stable oxidized 10-formylpteroylglutamate or to the reduced 5-formyl derivative. In contrast 5-methyltetrahydropteroylglutamate was much less stable nutritionally than expected.Unsubstituted tetrahydropteroylglutamate was most unstable nutritionally but in contrast to the other derivatives examined it was more stable under acidic than basic conditions. Ascorbate was found to be a far superior stabilizing agent than 2-mercaptoethanol at comparable concentrations. PMID:236647

  18. Experimental and Theoretical Investigations of Spectral, Tautomerism and Acid-Base Properties of Schiff Bases Derived from Some Amino Acids

    Ebead, Y. H.; Salman, H. M. A.; Abdellah, M. A. [South Valley University, Qena (Egypt)

    2010-04-15

    The electronic absorption spectra of five Schiff bases derived from 2-hydroxy-1-naphthaldehyde with glycine, alanine, leucine, valine and phenylalanine have been measured in various solvents. The observed bands were assigned to the proper electronic transitions and compared with the predicted transitions at the semiempirical level of theory. The calculated equilibrium constants are in agreement with the experimental results, predicting the existence of all studied compounds predominantly or completely in keto-imine tautomerism. On the other hand, a correlation between ν (cm{sup -1}) (main frequency of each compound) and the well known solvent parameters E{sub T} (30), ε{sub r}, π* has been made. Furthermore, the acid dissociation constants, pK{sub a}, were determined by using three different spectrophotometric methods.

  19. Molecular markers derived from bombesin for tumor diagnosis by SPECT and PET

    A high number of molecules have already been identified to have high affinity to some receptors overexpressed on tumour cells and the radiolabelling of those molecules offers the possibility of new compounds for tumour diagnosis and therapy by nuclear medicine. Among of those molecules, bombesin (BBN) has become focus of interest, as its BB2 receptors are known to be overexpressed in prostate, breast, colon, pancreatic and lung tumour, as long as glioblastomas and neuroblastomas. BBN agonists and antagonists have already been described for this purpose and promising results were obtained in preclinical studies. However, most of them exhibited high abdominal accumulation, especially in pancreas and intestines, which can compromise diagnosis accuracy and cause serious adverse effects in therapy. In this context, the goal of the present work to radiolabel new BBN derivatives with 111In and 68Ga and to evaluate their potential for BB2 positive tumors diagnosis by single photon emission tomography (SPECT) and positron emission tomography (PET). The structure of studied peptides was Q-YGn-BBN(6-14), where Q is the chelator, n is the number of glycine aminoacids in the spacer YGn and BBN(6-14) is the original bombesin sequence from the aminoacid 6 to 14. The derivative in which the last aminoacid (methionine, Met) was replaced by norleucine (Nle) was also evaluated. The experimental evaluation of the bombesin derivatives was divided into four steps: computational studies, molecular markers for SPECT, molecular markers for PET and toxicological studies. The theoretical partition (log P) and distribution (log D) coefficients were calculated for all bombesin derivatives conjugated to DTPA (diethylenetriaminepentaacetic acid) and DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) chelators applying computational programmes. Bombesin derivatives for SPECT were developed by radiolabelling DTPA-conjugated bombesin derivatives with 111In to determine the best spacer

  20. "Protective Effects of Some Azo Derivatives of 5-aminosalicylic Acid and Their Pegylated Prodrugs on Acetic Acid-induced Rat Colitis "

    Alireza Garjani; Soodabeh Davaran; Mohamadreza Rashidi; Nasrin Malek

    2004-01-01

    The protective and anti-inflammatory effects of azo and azo-linked polymeric prodrugs of 5-aminosalicylic acid (5-ASA) on acetic acid induced colitis in rats were investigated. Three azo prodrugs; 4,4 -dihydroxy-azobenzene-3-carboxilic acid (azo compound I), 4-hydroxy-azobenzene-3,4-dicarboxilic acid (azo compound II), 4,4-dihydroxy-3-formyl-azobenzene-3-carboxylic acid (azo compound III) and their polyethylene glycol (PEG 6000) derivatives were synthesized. Rats were pretreated orally (1 hou...

  1. 韩国能否改变DOTA2格局?

    尼博

    2013-01-01

    在世界电竞格局中,韩国一直是位列前茅的电竞强国。从最初的SC,到后来的War3,再到如今的SC2与LOL,韩国人在各个电竞项目中都取得了惊人的成就。随着DOTA2的来临,韩国已经正式进军DOTA2,在不久的将来,韩国人必将在DOTA2中掀起一阵血雨腥风。

  2. GMP production of 68Ga-labelled DOTA-NOC on IBA Synthera

    68Ga labelled peptides are increasingly being used clinically due to widespread availability of 68Ge/68Ga generators and their recognised importance in the diagnosis of neuroendocrine tumours. A simple and reproducible GMP-compliant process for labelling peptides with generator-produced 68Ga is crucial to meet current pharmaceutical requirements. Here, we describe the development of a cassette-based 68Ga-radiolabelling process using an automated commercial synthesizer coupled with a standard 68Ge/68Ga generator. The radiolabeled somatostatin analogue [68Ga]DOTA-NOC was successfully synthesized in about 30 min with 80.3 - 3.20 % of decay corrected radiochemical yield. The process is easily adaptable to the labelling of other peptides such as DOTA-TOC or DOTA-TATE for diagnosis or therapy. (author)

  3. Gd-DOTA: Preliminary pharmacologic results of a new contrast agent in MR

    Gd-DOTA is the most stable complex of gadolinium known at present. Its physico-chemical and toxicologic properties are compatible with future in vivo use (stability: K = 10/sup 28/; relaxivity R1 (270 MHz) = 3.5 mmol/sup -1/ . sec/sup -1/, LD50 when injected intravenously into mice = 11 mmol . kg/sup -1/). A crossover experiment conducted in 18 rabbits and six dogs injected intravenously with Gd-DOTA meglumine or Gd-DTPA dimeglumine showed no statistical difference in elimination parameters with variations in injected doses (0.1 mmol . kg/sup -1/ and 0.5 mmol . kg/sup -1/), species, or products. No target organ has been found, and the two products are rapidly eliminated almost exclusively by the kidney. Gd-DOTA appears to be a safe potential MR imaging contrast agent

  4. Comparison of sequential planar {sup 177}Lu-DOTA-TATE dosimetry scans with {sup 68}Ga-DOTA-TATE PET/CT images in patients with metastasized neuroendocrine tumours undergoing peptide receptor radionuclide therapy

    Sainz-Esteban, Aurora; Carril, Jose Manuel [Hospital Universitario Marques de Valdecilla, Department of Nuclear Medicine, Santander (Spain); Prasad, Vikas; Schuchardt, Christiane; Zachert, Carolin; Baum, Richard P. [Zentralklinik Bad Berka, Department of Nuclear Medicine and Centre for PET/CT, Bad Berka (Germany)

    2012-03-15

    The aim of the study was to compare sequential {sup 177}Lu-DOTA-TATE planar scans ({sup 177}Lu-DOTA-TATE) in patients with metastasized neuroendocrine tumours (NET) acquired during peptide receptor radionuclide therapy (PRRT) for dosimetry purposes with the pre-therapeutic {sup 68}Ga-DOTA-TATE positron emission tomography (PET)/CT ({sup 68}Ga-DOTA-TATE) maximum intensity projection (MIP) images obtained in the same patients concerning the sensitivity of the different methods. A total of 44 patients (59 {+-} 11 years old) with biopsy-proven NET underwent {sup 68}Ga-DOTA-TATE and {sup 177}Lu-DOTA-TATE imaging within 7.9 {+-} 7.5 days between the two examinations. {sup 177}Lu-DOTA-TATE planar images were acquired at 0.5, 2, 24, 48 and 72 h post-injection; lesions were given a score from 0 to 4 depending on the uptake of the radiopharmaceutical (0 being lowest and 4 highest). The number of tumour lesions which were identified on {sup 177}Lu-DOTA-TATE scans (in relation to the acquisition time after injection of the therapeutic dose as well as with regard to the body region) was compared to those detected on {sup 68}Ga-DOTA-TATE studies obtained before PRRT. A total of 318 lesions were detected; 280 (88%) lesions were concordant. Among the discordant lesions, 29 were {sup 68}Ga-DOTA-TATE positive and {sup 177}Lu-DOTA-TATE negative, whereas 9 were {sup 68}Ga-DOTA-TATE negative and {sup 177}Lu-DOTA-TATE positive. The sensitivity, positive predictive value and accuracy for {sup 177}Lu-DOTA-TATE as compared to {sup 68}Ga-DOTA-TATE were 91, 97 and 88%, respectively. Significantly more lesions were seen on the delayed (72 h) {sup 177}Lu-DOTA-TATE images (91%) as compared to the immediate (30 min) images (68%). The highest concordance was observed for bone metastases (97%) and the lowest for head/neck lesions (75%). Concordant lesions (n = 77; mean size 3.8 cm) were significantly larger than discordant lesions (n = 38; mean size 1.6 cm) (p < 0.05). No such significance was

  5. Salt-inducible promoter derivable from a lactic acid bacterium, and its use in a lactic acid bacterium for production of a desired protein

    Sanders, Jan Willem; Kok, Jan; Venema, Gerard; Ledeboer, Adrianus Marinus

    1998-01-01

    The invention provides a salt-inducible promoter present in SEQ ID NO: 10 and derivable from a lactic acid bacterium in isolation from the coding sequence normally controlled by said promoter in a wild-type lactic acid bacterium, with modifications and important parts thereof. Also provided are a re

  6. Effects of amino acid derivatives on physical, mental, and physiological activities.

    Luckose, Feby; Pandey, Mohan Chandra; Radhakrishna, Kolpe

    2015-01-01

    Nutritional ergogenic aids have been in use for a long time to enhance exercise and sports performance. Dietary components that exhibit ergogenic activity are numerous and their consumption is common and popular among athletes. They often come under scrutiny by legal authorities for their claimed benefits and safety concerns. Amino acid derivatives are propagated as being effective aids to enhance physical and mental performance in many ways, even though studies have pointed out that individuals who are deficient are more likely to benefit from dietary supplementation of amino acid derivatives than normal humans. In this review, some of the most common and widely used amino acids derivatives in sports and athletics namely creatine, tyrosine, carnitine, HMB, and taurine have been discussed for their effects on exercise performance, mental activity as well as body strength and composition. Creatine, carnitine, HMB, and taurine are reported to delay the onset of fatigue, improve exercise performance, and body strength. HMB helps in increasing fat-free mass and reduce exercise induced muscle injury. Taurine has been found to reduce oxidative stress during exercise and also act as an antihypertensive agent. Although, studies have not been able to find any favorable effect of tyrosine administration on exercise performance, it has been proved to be very effective in fighting stress, improving mood and cognitive performance particularly in sleep-deprived subjects. While available data from published studies and findings are equivocal about the efficacy of creatine, tyrosine, and HMB, more comprehensive researches on carnitine and taurine are necessary to provide evidence for the theoretical basis of their ergogenic role in nutritional modification and supplementation. PMID:24279396

  7. Bioactive 1,4-dihydroisonicotinic acid derivatives prevent oxidative damage of liver cells.

    Borovic, Suzana; Tirzitis, Gunars; Tirzite, Dace; Cipak, Ana; Khoschsorur, Gholam A; Waeg, Georg; Tatzber, Franz; Scukanec-Spoljar, Mira; Zarkovic, Neven

    2006-05-10

    1,4-Dihydroisonicotinic acid derivatives (1,4-DHINA) are compounds closely related to derivatives of 1,4-dihydropyridine, a well-known calcium channel antagonists. 1,4-DHINA we used were derived from a well-known antioxidant Diludin. Although some compounds have neuromodulatory or antimutagenic properties, their activity mechanisms are not well known. This study was performed to obtain data on antioxidant and bioprotective activities of: 2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydroisonicotinic acid (Ia); sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)glutamate (Ib) and sodium 2-(2,6-dimethyl-3,5-diethoxycarbonyl-1,4-dihydropyridine-4-carboxamido)ethane-sulphate (Ic). 1,4-DHINA's activities were studied in comparison to Trolox by: N,N-Diphenyl-N'-picrylhydrazyl (DPPH*), deoxyribose degradation, 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS) radical scavenging and antioxidative capacity assays; copper-induced lipid peroxidation of cultured rat liver cells (malondialdehyde determination by high performance liquid chromatography and 4-hydroxynonenal-protein conjugates by dot-blot); (3)H-thymidine incorporation and trypan blue assay for liver cells growth and viability. In all assays used Ia was the most potent antioxidant. Ia was also a potent antioxidant at non-toxic concentrations for liver cell cultures. It completely abolished, while Ic only slightly decreased copper-induced lipid peroxidation of liver cells. Thus, antioxidant capacities are important activity principle of Ia, which was even superior to Trolox in the cell cultures used, while activity principles of Ic and Ib remain yet to be determined. PMID:16600211

  8. Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives

    Isabel Bento

    2006-11-01

    Full Text Available A series of indazoles substituted at the N-1 and N-2 positions with ester-containing side chains -(CH2nCO2R of different lengths (n = 0-6, 9, 10 are described.Nucleophilic substitution reactions on halo esters (X(CH2nCO2R by 1H-indazole inalkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomerpredominates. Basic hydrolysis of the ester derivatives allowed the synthesis of thecorresponding indazole carboxylic acids. All compounds were fully characterised bymultinuclear NMR and IR spectroscopies, MS spectrometry and elemental analysis; theNMR spectroscopic data were used for structural assignment of the N-1 and N-2 isomers.The molecular structure of indazol-2-yl-acetic acid (5b was determined by X-raydiffraction, which shows a supramolecular architecture involving O2-H...N1intermolecular hydrogen bonds.

  9. Molecular interaction of acetylcholinesterase with carnosic acid derivatives: a neuroinformatics study.

    Merad, M; Soufi, W; Ghalem, S; Boukli, F; Baig, M H; Ahmad, K; Kamal, Mohammad A

    2014-04-01

    Alzheimer's disease is a progressive degenerative disease of the brain marked by gradual and irreversible declines in cognitive functions. Acetylcholinesterase (AChE) plays a biological role in the termination of nerve impulse transmissions at cholinergic synapses by rapid hydrolysis of its substrate, "acetylcholine". The deficit level of acetylcholine leads to deprived nerve impulse transmission. Thus the cholinesterase inhibitors would reverse the deficit in acetylcholine level and consequently may reverse the memory impairments, which is characteristic of the Alzheimer's disease. The molecular interactions between AChE and Carnosic acid, a well known antioxidant substance found in the leaves of the rosemary plant has always been an area of interest. Here in this study we have performed in silico approach to identify carnosic acid derivatives having the potential of being a possible drug candidate against AChE. The best candidates were selected on the basis of the results of different scoring functions. PMID:24059305

  10. Strecker degradation of amino acids promoted by a camphor-derived sulfonamide.

    Carvalho, M Fernanda N N; Ferreira, M João; Knittel, Ana S O; Oliveira, Maria da Conceição; Costa Pessoa, João; Herrmann, Rudolf; Wagner, Gabriele

    2016-01-01

    A camphor-derived sulfonimine with a conjugated carbonyl group, oxoimine 1 (O2SNC10H13O), reacts with amino acids (glycine, L-alanine, L-phenylalanine, L-leucine) to form a compound O2SNC10H13NC10H14NSO2 (2) which was characterized by spectroscopic means (MS and NMR) and supported by DFT calculations. The product, a single diastereoisomer, contains two oxoimine units connected by a -N= bridge, and thus has a structural analogy to the colored product Ruhemann´s purple obtained by the ninhydrin reaction with amino acids. A plausible reaction mechanism that involves zwitterions, a Strecker degradation of an intermediate imine and water-catalyzed tautomerizations was developed by means of DFT calculations on potential transition states. PMID:27340465

  11. Strecker degradation of amino acids promoted by a camphor-derived sulfonamide

    Ferreira, M João; Knittel, Ana S O; Oliveira, Maria da Conceição; Costa Pessoa, João; Herrmann, Rudolf; Wagner, Gabriele

    2016-01-01

    Summary A camphor-derived sulfonimine with a conjugated carbonyl group, oxoimine 1 (O2SNC10H13O), reacts with amino acids (glycine, L-alanine, L-phenylalanine, L-leucine) to form a compound O2SNC10H13NC10H14NSO2 (2) which was characterized by spectroscopic means (MS and NMR) and supported by DFT calculations. The product, a single diastereoisomer, contains two oxoimine units connected by a –N= bridge, and thus has a structural analogy to the colored product Ruhemann´s purple obtained by the ninhydrin reaction with amino acids. A plausible reaction mechanism that involves zwitterions, a Strecker degradation of an intermediate imine and water-catalyzed tautomerizations was developed by means of DFT calculations on potential transition states.

  12. Synthesis, structure and complex formation properties of alkyl derivatives of ethylxantogenic acids

    Full text: The representatives of many classes of organic compounds are tested as analytical reactants, in particular, extractants of different metal ions. But majority of investigated substances does not have selectivity in relation to given metal ions. Therefore with the purpose of discovering selective extractants for noble metals, alkyl derivatives of xanthogenic acid are synthesized: RX + K - S - C (S) OC2H5 → R - S - C (S) OC2H5 + KX. R = C3H7 - C7H15, i-C4H9; X = Cl, Br. In an IR - spectrum of xanthogenic acid derivatives there are absorption bands of following functional groups (ν, cm-1): (-CH2, CH3) 2850-2950, (C-S) 650, (C-O-C) 1030 and 1210. In a H1 NMR spectrum of S-butylxantogenate, a quartet of OCH2- group, with a constant of a spin-spin interaction J = 6,6 Hz, is observed at 4,56 p.m., whereas a triplet of S-CH2 - group (J = 6,5 Hz) is at 3,07 p.m. The protons C-CH2 of groups (4H) are observed as a multiplet at 1,6-1,7 p.m., and the multiplet signals of CH3 - group are located at 1,35 p.m. A triplet signal at 0,95 p.m. belong to the three protons of CH3 - group. Solving the mass spectrum of S-amylxantogenate has shown that the decay of a molecular ion takes place in different directions and the destruction of C-S - bond causes formation in the spectrum of the most intensive ion with m/z 122 (100 %). The ion [M + H] has lower intensity (m/z 193, 26,85 %). Upon decay of an ion m/z 122 the intensive ions with m/z 77 (18,52 %), 89 (74,07 %) and 61 (96,3 %) are formed. At a mass spectrum of this substance there is also a signal of [M-H] + ion (16,1 %). The destruction of C-S -bond causes the formation of the most intensive ion with m/e 122 (100 %). Upon destruction of C-C bond of alkyl chain the ions with m/z 177 (0,5 %) are formed. During fragmentation of a molecular ion the ions with 77 (18,52 %) are formed, and also ions with m/z 89 (44,44 %) and 61 (96,3 %), whose signals are distinguished by high intensity. As the obtained data show, the

  13. Amino-modified tetraphenylethene derivatives as nucleic acid stain: relationship between the structure and sensitivity.

    Xu, Li; Zhu, Zece; Wei, Danqing; Zhou, Xiang; Qin, Jingui; Yang, Chuluo

    2014-10-22

    A series of new amino-functionalized tetraphenylethene (TPE) derivatives were designed and synthesized to study the effect of molecular structures on the detection of nucleic acid. Contrastive studies revealed that the number of binding groups, the length of hydrophobic linking arm and the configuration of TPE molecule all play important roles on the sensitivity of the probes in nucleic acid detection. Z-TPE3 with two binding amino groups, long linking arms, and cis configuration was found to be the most sensitive dye in both solution and gel matrix. Z-TPE3 is able to stain dsDNA with the lowest amount of 1 ng and exclusively stain 40 ng of short oligonucleotide with only 10 nt. This work is of important significance for the further design of TPE probes as biosensors with higher sensitivity. PMID:25279446

  14. Preparation and Physical Properties of Chitosan Benzoic Acid Derivatives Using a Phosphoryl Mixed Anhydride System

    Kyu Yun Chai

    2012-02-01

    Full Text Available Direct benzoylation of the two hydroxyl groups on chitosan was achieved using a phosphoryl mixed anhydride system, derived from trifluoroacetic anhydride (TFAA, benzoic acids (BAs, and phosphoric acid (PA. The reaction is operated as a one pot process under mild conditions that does not require neither an inert atmosphere nor dry solvents. The structures of the synthesized compounds were confirmed by NMR and IR spectroscopy. Solubility tests on the products revealed that they were soluble in organic solvents such as N,N-dimethylformamide (DMF, dimethylsulfoxide (DMSO, and acetone. In the meantime, a morphological study by scanning electron microscopy (SEM evidently indicated that the chitosan benzoates underwent significant structural changes after the benzoylation.

  15. Solution structure of human acidic fibroblast growth factor and interaction with heparin-derived hexasaccharide

    Fibroblast growth factors (FGFs) bind to extracellular matrices, especially heparin-like carbohydrates of heparansulfate proteoglycans which stabilize FGFs to protect against inactivation by heat, acid, proteolysis and oxidation. Moreover, binding of FGFs to cell surface proteoglycans promotes to form oligomers, which is essential for receptor oligomerization and activation. In the present study, we determined the solution structure of acidic FGF using a series of triple resonance multi-dimensional NMR experiments and simulated annealing calculations. Furthermore, we prepared the sample complexed with a heparin-derived hexasaccharide which is a minimum unit for aFGF binding. From the chemical shift differences between free aFGF and aFGF-heparin complex, we concluded that the major heparin binding site was located on the regions 110-131 and 17-21. The binding sites are quite similar to those observed for bFGF-heparin hexasaccharide complex, showing that both FGFs recognize heparin- oligosaccharides in a similar manner

  16. Green Synthesis and Urease Inhibitory Activity of Spiro-Pyrimidinethiones/Spiro-Pyrimidinones-Barbituric Acid Derivatives.

    Mohammadi Ziarani, Ghodsi; Asadi, Shima; Faramarzi, Sakineh; Amanlou, Massoud

    2015-01-01

    Sulfonic acid functionalized SBA-15 (SBA-Pr-SO3H) with pore size 6 nm as an efficient heterogeneous nanoporous solid acid catalyst exhibited good catalytic activity in the Biginelli-like reaction in the synthesis of spiroheterobicyclic rings with good yield and good recyclability. Spiro-pyrimidinethiones/spiro-pyrimidinones-barbituric acid derivatives were synthesized in a simple and efficient method using the one-pot three-component reaction of a cyclic 1,3- dicarbonyl compounds (barbituric acid), an aromatic aldehyde and urea or thiourea in the presence of nanoporous silica SBA-Pr-SO3H under solvent free conditions. Urease inhibitory activity of spiro compounds were tested against Jack bean urease using Berthelot alkaline phenol-hypochlorite method. Five of 13 compounds were inhibitor and two of them were enzyme activators. Analysis of the docking results showed that, in most of the spiro molecules, one of the carbonyl groups is coordinated with both nickel atoms, while the other one is involved in the formation of hydrogen bonds with important active-site residues. The effect of inserting two methyl groups on N atoms of barbiturate ring, S substituted, ortho, meta and para substituted compounds were investigated too. PMID:26664377

  17. Recent progress in electrochemical biosensors based on phenylboronic acid and derivatives.

    Anzai, Jun-Ichi

    2016-10-01

    This review provides an overview of recent progress made in the development of electrochemical biosensors based on phenylboronic acid (PBA) and its derivatives. PBAs are known to selectively bind 1,2- and 1,3-diols to form negatively charged boronate esters in neutral aqueous media and have been used to construct electrochemical glucose sensors because of this selective binding. PBA-modified metal and carbon electrodes have been widely studied as voltammetric and potentiometric glucose sensors. In some cases, ferroceneboronic acid or ferrocene-modified phenylboronic acids are used as sugar-selective redox compounds. Another option for sensors using PBA-modified electrodes is potentiometric detection, in which the changes in surface potential of the electrodes are detected as an output signal. An ion-sensitive field effect transistor (FET) has been used as a signal transducer in potentiometric sensors. Glycoproteins, such as glycated hemoglobin (HbA1c), avidin, and serum albumin can also be detected by PBA-modified electrodes because they contain hydrocarbon chains on the surface. HbA1c sensors are promising alternatives to enzyme-based glucose sensors for monitoring blood glucose levels over the preceding 2-3months. In addition, PBA-modified electrodes can be used to detect a variety of compounds including hydroxy acids and fluoride (F(-)) ions. PBA-based F(-) ion sensors may be useful if reagentless sensors can be developed. PMID:27287174

  18. Uptake of acidic and basic sugar derivatives in Lemna gibba G1

    The uptake of acidic and basic sugar derivatives in Lemna gibba L. was studied. Uronic acids applied to the experimental solution induced a small decrease of the membrane potential. After incubation of the plants in a 0.1 millimolar solution of these substrates, no decrease in the concentration of reducing groups in the external solution was detected. Respiration increased by 31% with 50 millimolar galacturonic acid, whereas no effect was found with the same concentration of glucuronic acid. Glucosamine caused a considerable concentration-dependent membrane depolarization. (14C)glucosamine uptake followed Michaelis-Menten kinetics together with a linear component. Influx of this substrate was inhibited by glucose but the type of competition could not be clearly distinguished. Glucosamine, 50 millimolar, inhibited the respiration rate by 30%. The glucosamine uptake was pH-dependent, with maximum uptake at around pH 7. Lack of enhancement of uptake by low pH as well as the permanent membrane depolarization suggest a uniport mechanism for the charged species of the substrate and an electroneutral diffusion of the uncharged species

  19. Controlled synthesis and inclusion ability of a hyaluronic acid derivative bearing beta-cyclodextrin molecules.

    Charlot, Aurélia; Heyraud, Alain; Guenot, Pierre; Rinaudo, Marguerite; Auzély-Velty, Rachel

    2006-03-01

    A new synthetic route to beta-cyclodextrin-linked hyaluronic acid (HA-CD) was developed. This was based on the preparation of a HA derivative selectively modified with adipic dihydrazide (HA-ADH) and a beta-cyclodextrin derivative possessing an aldehyde function on the primary face, followed by their coupling by a reductive amination-type reaction. The CD-polysaccharide was fully characterized in terms of chemical integrity and purity by high-resolution NMR spectroscopy. The complexation ability of the grafted CD was further demonstrated by isothermal titration calorimetry using sodium adamantane acetate (ADAc) and Ibuprofen as model guest molecules. The thermodynamic parameters for the complexation of these negatively charged guest molecules by the beta-CD grafted on negatively charged HA were shown to be largely influenced by the ionic strength of the aqueous medium. PMID:16529430

  20. Synthesis and Anti-tumor Activity of Novel Glycyrrhetinic Acid Derivatives

    MENG Yan-qiu; DING Jia-qi; LIU Yuan; NIE Hui-hui; GUAN Sai; ZOU Chao; ZHAO Na; CHEN Hong; CAO Bo

    2012-01-01

    Twenty-five derivatives of glycyrrhetinic acid(GA)modified on the A-ring,at C30 and C11 positions were synthesized.Their in vitro cytotoxicity against various cancer cell lines[henrietta lacks strain of cancer cells(HeLa),human hepatocellular liver carcinoma cells(HepG2)and human gastric carcinoma cells(BGC-823)]was evaluated by standard MTT[3-(4,5-dimethyl-2-thiazol-yl)-2,5-diphenyl-2H-tetrazolium bromide]assay.All the tested derivatives were found to have stronger cell growth inhibitory than their parent compound GA.Among them,compounds 3a,5a,and 8d have similar activity on HeLa cell line,and compound 8a has similar activity on HeLa,HepG2 and BGC-823 cell lines as Gefitinib.

  1. Arachidonic Acid Derivatives and Their Role in Peripheral Nerve Degeneration and Regeneration

    Carlos Rodrigo Camara-Lemarroy

    2012-01-01

    Full Text Available After peripheral nerve injury, a process of axonal degradation, debris clearance, and subsequent regeneration is initiated by complex local signaling, called Wallerian degeneration (WD. This process is in part mediated by neuroglia as well as infiltrating inflammatory cells and regulated by inflammatory mediators such as cytokines, chemokines, and the activation of transcription factors also related to the inflammatory response. Part of this neuroimmune signaling is mediated by the innate immune system, including arachidonic acid (AA derivatives such as prostaglandins and leukotrienes. The enzymes responsible for their production, cyclooxygenases and lipooxygenases, also participate in nerve degeneration and regeneration. The interactions between signals for nerve regeneration and neuroinflammation go all the way down to the molecular level. In this paper, we discuss the role that AA derivatives might play during WD and nerve regeneration, and the therapeutic possibilities that arise.

  2. [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate: comparison with [{sup 111}In-DTPA{sup 0}]octreotide in patients

    Kwekkeboom, D.J.; Bakker, W.H.; Kooij, P.P.M.; De Jong, M. [Dept. of Nuclear Medicine, Univ. Hospital Rotterdam (Netherlands); Konijnenberg, M.W. [Mallinckrodt Medical, Petten (Netherlands); Srinivasan, A.; Erion, J.L.; Schmidt, M.A.; Bugaj, J.L. [Mallinckrodt Medical, St. Louis, MO (United States); Krenning, E.P. [Dept. of Nuclear Medicine, Univ. Hospital Rotterdam (Netherlands); Dept. of Internal Medicine, University Hospital Rotterdam (Netherlands)

    2001-09-01

    The somatostatin analogue [DOTA{sup 0},Tyr{sup 3}]octreotate has a nine-fold higher affinity for the somatostatin receptor subtype 2 as compared with [DOTA{sup 0},Tyr{sup 3}]octreotide. Also, labelled with the beta- and gamma-emitting radionuclide lutetium-177, this compound has been shown to have a very favourable impact on tumour regression and animal survival in a rat model. Because of these reported advantages over the analogues currently used for somatostatin receptor-mediated radiotherapy, we decided to compare [{sup 177}Lu-DOTA{sup 0},Tyr{sup 3}]octreotate ({sup 177}Lu-octreotate) with [{sup 111}In-DTPA{sup 0}]octreotide ({sup 111}In-octreotide) in six patients with somatostatin receptor-positive tumours. Plasma radioactivity after {sup 177}Lu-octreotate expressed as a percentage of the injected dose was comparable with that after {sup 111}In-octreotide. Urinary excretion of radioactivity was significantly lower than after {sup 111}In-octreotide, averaging 64% after 24 h. The uptake after 24 h, expressed as a percentage of the injected dose of {sup 177}Lu-octreotate, was comparable to that after {sup 111}In-octreotide for kidneys, spleen and liver, but was three- to fourfold higher for four of five tumours. The spleen and kidneys received the highest absorbed doses. The doses to the kidneys were reduced by a mean of 47% after co-infusion of amino acids. It is concluded that in comparison with the radionuclide-coupled somatostatin analogues that are currently available for somatostatin receptor-mediated radiotherapy, {sup 177}Lu-octreotate potentially represents an important improvement. Higher absorbed doses can be achieved to most tumours, with about equal doses to potentially dose-limiting organs; furthermore, the lower tissue penetration range of {sup 177}Lu as compared with {sup 90}Y may be especially important for small tumours. (orig.)

  3. Phase II trial of yttrium-90-DOTA-biotin pretargeted by NR-LU-10 antibody/streptavidin in patients with metastatic colon cancer

    A Phase II study of yttrium-90-tetra-azacyclododecanetetra-acetic acid-biotin (Y-90-DOTA-biotin) pretargeted by NR-LU-10 antibody/streptavidin (SA) was performed. The primary objectives of the study were to evaluate the efficacy and safety of this therapy in patients with metastatic colon cancer. Twenty-five patients were treated with a single dose of 110 mCi/m2 (mean administered dose, 106.5-10.3 mCi/m2) of Y-90-DOTA-biotin. There were three components of the therapy. Patients first received NR-LU-10/SA on day 1. A clearing agent (biotin-galactose-human serum albumin) was administered 48 h after the NR-LU-10/SA to remove residual circulating unbound NR-LU-10/SA. Lastly, 24 h after administration of clearing agent, patients received biotin-DOTA-labeled with 110 mCi/m2 Y-90. All three components of the therapy were administered i.v. Both hematological and nonhematological toxicities were observed. Diarrhea was the most frequent grade 4 nonhematological toxicity (16%; with 16% grade 3 diarrhea). Hematological toxicity was less severe with 8% grade 3 and 8% grade 4 neutropenia and 8% grade 3 and 16% grade 4 thrombocytopenia. The overall response rate was 8%. Two partial responders had freedom from progression of 16 weeks. Four patients (16%) had stable disease with freedom from progression of 10-20 weeks. Despite the relatively disappointing results of this study in terms of therapeutic efficacy and toxicity, proof of principle was obtained for the pretargeting approach. In addition, valuable new information was obtained about normal tissue tolerance to low-dose-rate irradiation that will help to provide useful guidelines for future study designs

  4. Polycarboxylate derivative of -amino acid as growth modifier of sulphide minerals

    Harjyoti Thakuria; Gopal Das

    2011-02-01

    Construction of modified inorganic mineral with controlled mineralization analogues of those produced by nature is now of current interest for understanding the mechanism of the in vivo biomineralization processes, as well as looking for fresh industrial and technological applications. Low-molecular-weight chiral polycarboxylate ligands derived fromnaturally occurring -\\alpha-amino acids have been used asmodel systems to study the effect of small organic matrix on crystal growth modification. The sulphide minerals are characterized by PXRD, FT–IR and SEM. Furthermore, the optical properties of these minerals have been characterized by UV-Vis and photoluminescence (PL) spectra.

  5. Myrsinoic A acid and its derivative: in vitro inhibitors of photosynthesis

    Myrsinoic A acid, isolated from Myrsine cuneifolia and its hydrogenated derivative had their effect on photosynthesis tested. The compounds inhibited the electron flow (basal, phosphorylating and uncoupled) from water to methyl viologen; therefore, they act as Hill reaction inhibitors in spinach thylakoids. They inhibited partial reactions of PSII electron flow from water to 2,5-dichloro-1,4-benzoquinone, from water to sodium silicomolybdate, and partially electron flow from diphenylcarbazide to 2,6-dichloroindophenol. Their inhibition sites were at the donor and acceptor sides of PSII, between P680 and QA. Chlorophyll α fluorescence measurements confirmed the behavior of the compounds (pool of quinones). (author)

  6. Further exploration of antimicrobial ketodihydronicotinic acid derivatives by multiple parallel syntheses

    Laursen, Jane B.; Nielsen, Janne; Haack, T.;

    2006-01-01

    synthetic manner and these were examined in vitro for their antimicrobial potential. Several compounds demonstrated significant broad-spectrum activity against clinically derived bacterial strains but previously known 1-(2,4-difluorophenyl)-6-(4-dimethylaminophenyl)-4-pyridone-3-carboxylic acid (7) remained...... the most potent compound in this class. Cross-resistance with ciprofloxacin supported a commonality of mode of action. Permiabilization of Escherichia coli cells by polymyxin B significantly enhanced potency with these agents suggesting that poor cellular uptake was primarily responsible for the...

  7. Oxidation of some disubstituted anisole derivatives with ceric perchlorate in perchloric acid solution

    The influence of concentration of particular reagents on the kinetics of Ce(IV) reduction by 2,6-dimethyl and 3,5-dimethyl-anisole as well as 2-methoxy-5-methyl- and 4-methoxy-2-methyl-aniline in perchloric acid solution was investigated, establishing the stoichiometry of these processes. Some intermediate products - macromolecular, derivatives of p-benzoquinone and 4,4'-diphenoquinone - were separated and identified. The effects of substituents and the conditions of performed oxidation processes on the kind and yields of the resultant products were considered. (author). 22 refs, 1 fig., 1 tab

  8. Synthesis and Antitumor Activity of Amino Acid Ester Derivatives Containing 5-Fluorouracil

    Jing Xiong

    2009-08-01

    Full Text Available A series of amino acid ester derivatives containing 5-fluorouracil were synthesized using 1-ethyl-3-(3-dimethylaminopropylcarbodiimide hydrochloride (EDC•HCl and N-hydroxybenzotriazole (HOBt as a coupling agent. The structures of the products were assigned by NMR, MS, IR etc. The in vitro antitumor activity tests against leukaemia HL-60 and liver cancer BEL-7402 indicated that (R-ethyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H-ylacetamido-3-(4-hydroxyphenyl propanoate showed more inhibitory effect against BEL-7402 than 5-FU.

  9. Design and Synthesis of a Dual Linker for Solid Phase Synthesis of Oleanolic Acid Derivatives

    Shaorong Wang

    2011-06-01

    Full Text Available A hydrophilic amino-terminated poly(ethylene glycol-type dual linker for solid phase synthesis of oleanolic acid derivatives using trityl chloride resin was designed and synthesized for the first time. Model reactions in both liquid and solid phase were performed to show the feasibility of its selective cleavage at two different sites. The biological assay results indicated that the long and flexible alkyl ether functionality in the linker is less likely to be critical for the binding event. Following the successful solid-phase synthesis of model compounds, the potential of this dual linker in reaction monitoring and target identification is deemed worthy of further study.

  10. N-Hydroxypyrazolyl glycine derivatives as selective N-methyl-D-aspartic acid receptor ligands

    Clausen, Rasmus Prætorius; Christensen, Caspar; Hansen, Kasper Bø;

    2008-01-01

    glycine (NHP5G) derivatives are selectively recognized by N-methyl- d-aspartic acid (NMDA) receptors and that the ( R)-enantiomers are preferred. Moreover, several of the compounds are able to discriminate between individual subtypes among the NMDA receptors, providing new pharmacological tools. For......A series of analogues based on N-hydroxypyrazole as a bioisostere for the distal carboxylate group of aspartate have been designed, synthesized, and pharmacologically characterized. Affinity studies on the major glutamate receptor subgroups show that these 4-substituted N-hydroxypyrazol-5-yl...

  11. Visible-Light-Induced Decarboxylative Functionalization of Carboxylic Acids and Their Derivatives.

    Xuan, Jun; Zhang, Zhao-Guo; Xiao, Wen-Jing

    2015-12-21

    Visible-light-induced radical decarboxylative functionalization of carboxylic acids and their derivatives has recently received considerable attention as a novel and efficient method to create CC and CX bonds. Generally, this visible-light-promoted decarboxylation process can smoothly occur under mild reaction conditions with a broad range of substrates and an excellent functional-group tolerance. The radical species formed from the decarboxylation step can participate in not only single photocatalytic transformations, but also dual-catalytic cross-coupling reactions by combining photoredox catalysis with other catalytic processes. Recent advances in this research area are discussed herein. PMID:26509837

  12. Synthesis and Structural Characterization of 1- and 2-Substituted Indazoles: Ester and Carboxylic Acid Derivatives

    Isabel Bento; Teresa Duarte, M.; M. João M. Curto; Inês F. Antunes; Hélène Ramos; Fátima C. Teixeira

    2006-01-01

    A series of indazoles substituted at the N-1 and N-2 positions with ester-containing side chains -(CH2)nCO2R of different lengths (n = 0-6, 9, 10) are described.Nucleophilic substitution reactions on halo esters (X(CH2)nCO2R) by 1H-indazole inalkaline solution lead to mixtures of N-1 and N-2 isomers, in which the N-1 isomerpredominates. Basic hydrolysis of the ester derivatives allowed the synthesis of thecorresponding indazole carboxylic acids. All compounds were fully characterised bymultin...

  13. Determination of U(VI) and Pu(IV) in nitric acid solutions with derivative spectroscopy

    The authors study the absorption spectra and fourth derivative spectra (FDS) of U(VI) and Pu(IV) in nitric acid solutions and the effect of impurities on FDS. The concentrations of U(VI) and Pu(IV) with peak-zero method at 415 nm and peak-area method between 472.5-479.5 nm are determined, respectively. When CHNO3 or CNO3- is in 1.5-3.0 mol/l, U(VI) can be directly determined by FDS, with the analysis deviation -4 mol/l

  14. Synthesis and Biological Activity of Arylspiroborate Salts Derived from Caffeic Acid Phenethyl Ester

    Martin J. G. Hébert

    2015-01-01

    Full Text Available Two novel boron compounds containing caffeic acid phenethyl ester (CAPE derivatives have been prepared and characterized fully. These new compounds and CAPE have been investigated for potential antioxidant and antimicrobial properties and their ability to inhibit 5-lipoxygenase and whether chelation to boron improves their biological activity. Sodium salt 4 was generally more active than ammonium salt 5 in the biological assays and surpassed the radical scavenging ability of CAPE. Compounds 4 and 5 were more active than CAPE and Zileuton in human polymorphonuclear leukocytes. These results clearly show the effectiveness of the synthesized salts as transporter of CAPE.

  15. Adsorption of Free Fatty Acid from Crude Palm Oil on Magnesium Silicate Derived from Rice Husk

    Pornsawan Assawasaengrat; Prakob Kitchaiya; Weerawat Clowutimon

    2011-01-01

    Magnesium silicate with various silica and magnesium oxide ratios (SiO2/MgO ratios) was used as the adsorbent for a study of adsorption of free fatty acid (FFA) in crude palm oil (CPO). Magnesium silicate was prepared from magnesium nitrate or magnesium sulfate solution precipitated with a solution of sodium silicate derived from rice husk. SiO2/MgO ratios of the magnesium silicate synthesized from magnesium nitrate and magnesium sulfate were 3.93, 3.75, 2.74, 2.40, 1.99 and 3.96, 3.61, 3.51,...

  16. Identification of new quinic acid derivatives as histone deacetylase inhibitors by fluorescence-based cellular assay.

    Son, Dohyun; Kim, Chung Sub; Lee, Kang Ro; Park, Hyun-Ju

    2016-05-01

    A fluorescence-based cellular assay system was established to identify potential epigenetic modulator ligands. This assay method is to detect the de-repression of an EGFP reporter in cancer cells by the treatment of HDAC (histone deacetylase) or DNMT (DNA methyltransferase) inhibitor. Using this system, we conducted a preliminary screening of in-house natural product library containing extracts and pure compounds, and identified several active compounds. Among them, novel quinic acid derivatives were recognized as excellent HDAC inhibitors by both enzymatic and cell-based HDAC assays. PMID:26996372

  17. Wittig reaction (with ethylidene triphenylphosphorane) of oxo-hydroxy derivatives of 5β-cholanic acid: Hydrophobicity, haemolytic potential and capacity of derived ethylidene derivatives for solubilisation of cholesterol.

    Poša, Mihalj; Bjedov, Srđan; Sebenji, Ana; Sakač, Marija

    2014-08-01

    Bile acid salts are biosurfactants which form mixed micelles with phospholipids in vertebrates. These mixed micelles are suitable for solubilisation of cholesterol. For therapeutic purposes some bile acid salts as sodium ursocholate are used. However, bile acid anions possess low capacity for solubilisation of cholesterol. Thus, synthesis of more hydrophobic and less membranotoxic bile acid derivatives is of the great interest. In this paper Wittig reaction between ethylidene triphenylphosphorane and different bile acids oxo derivatives is examined. Wittig reaction of bile acids has not been studied much. C12 oxo group is inert in this reaction. If Wittig reaction happens on C7 oxo group stereospecifically E ethylidene stereoisomer is obtained, while the same reaction on C3 oxo group leads to more reactive not sterospecific product. In this paper stereochemical course of investigated Wittig reactions is thoroughly analysed. Hydrophobicity of derived products is determined over the temperature (T) dependence on retention coefficients (k) in reversed phase high resolution chromatography. Using method of principle components on k=f(T) matrix it is found that values of first principle components best describe hydrophobicity of analysed bile acids, while the second principal component is responsible for their hydrophilicity. By in silico molecular descriptors: valence connectivity index of order 3 (X3v) and packing density index (PDI), linear regression equations are obtained that can be used to predict hydrophobicity (over retention coefficient) of bile acids that belong to set of more congeneric groups. Membranotoxicity is determined by haemolytic potential. Monoethylidene derivatives of bile acids (in the form of anions) have lower membranotoxicity than deoxycholic acids anion. Sodium salt of deoxycholic acid 7-ethylidene derivative has 11% greater capacity for solubilisation of cholesterol monohydrate than sodium salt of deoxycholic acid. PMID:24819990

  18. Modeling of biodistribution of 90 Y-DOTA-hR3 by using artificial intelligence techniques

    In this work the biodistribution of radioimmunoconjugate 90Y-DOTA-hR3 was modeled by using an artificial neural network. In vivo stability of 90Y-DOTA-hR3 was determined in healthy male Wistar rats at 4, 24 and 48 hours, in different organs. A model describing the relationship between, by one hand, the incorporated dose and, by the other hand, organ and time was developed by using a multilayer perceptron neural network. Adjusted model was analyzed by several statistical tests. Outcomes shown that proposed neural model describes the relationship between the studied variables in a proper way. (Author)

  19. Klinische Wertigkeit der PET/CT mit 68Ga-DOTA-TOC bei Thymom und Thymuskarzinom

    Sander, Nathalie

    2015-01-01

    Zusammenfassung Ziel der vorliegenden Arbeit war es, die klinische Wertigkeit der PET/CT mit 68Ga-DOTA-TOC bei Thymomen und Thymuskarzinomen zu evaluieren. Diese Tumoren exprimieren typischerweise den Somatostatin-Rezeptor-Subtyp 2 (SSTR-2). In der Nuklearmedizin ermöglicht das Radiopeptid 68Ga-DOTA-TOC über die Positronen-Emissions-Tomographie (PET) die Darstellung der SSTR-2-Expression in vivo. In Verbindung mit der Computertomographie (CT) als Fusionstechnik (PET/CT) ist eine präzise a...

  20. Quantitation of flavanols, proanthocyanidins, isoflavones, flavanones, dihydrochalcones, stilbenes, and benzoic Acid derivatives after identification by LC-MS

    A general method was developed for the systematic quantitation of catechins, proanthocyanidins, isoflavones, flavanones, dihydrochalcones, stilbenes, and hydroxybenzoic acid derivatives (mainly hydrolyzable tannins) using the UV relative mole response factors (MRRF) of the reference standard from ea...

  1. Synthesis of 6-sulfamoyl-4-oxoquinoline-3-carboxylic acid derivatives as integrase antagonists with anti-HIV activity

    Zai Gang Luo; Cheng Chu Zeng; Lei Fu Yang; Hong Qiu He; Cun Xin Wang; Li Ming Hu

    2009-01-01

    A series of novel 6-sulfamoyl-4-oxoquinoline-3-earboxylic acids derivatives have been synthesized and screened for HIV integrase inhibition activity. Their structures were confirmed by ESI-MS, 1H NMR and 13C NMR.

  2. Evaluation of 177Lu-DOTA-labeled aglycosylated monoclonal anti-L1-CAM antibody chCE7: influence of the number of chelators on the in vitro and in vivo properties

    Introduction: In this study, we optimized the 1,4,7,10-tetraazacyclododecane-N-N'-N''-N''''-tetraacetic acid (DOTA) chelator-to-antibody (c/a) ratio for the aglycosylated variant of the anti-L1-CAM antibody chCE7 (chCE7agl), providing high specific activity and low liver uptake in 177Lu-labeled form. Methods: chCE7agl was substituted with increasing molar excess of DOTA-NCS. The number of chelators coupled to the antibody and the binding affinities to target tumor cells (IC5 values) of the resulting immunoconjugates were determined. The different immunoconjugates were labeled with 177Lu; specific activity was measured, and metabolic stability was analyzed in human plasma. The effect of different c/a ratios on blood clearance and liver uptake was tested in nude mice. Changes of the protein backbone structure were analyzed by circular dichroism spectroscopy. Results: chCE7agl was substituted with 7, 12 or 15 DOTA ligands. The IC5 concentrations displacing radioiodinated chCE7 antibody increased with the number of chelators (1.5-fold with 7 ligands, 2.5-fold with 12 ligands and a 5-fold increase with 15 ligands). The highest specific activity for 177Lu-DOTA-chCE7agl was obtained with a c/a ratio of 12 (106 MBq/mg). Radioimmunoconjugates were stable in human plasma for at least 24 h. Blood clearance and liver uptake were measured after 24 h (c/a ratios of 12 and 15) or 48 h (c/a ratio of 7). The liver-to-blood ratios were 0.35±0.14 (7 ligands), 0.77±0.19 (12 ligands) and 17.85±3.44 (15 ligands). Conclusions: DOTA-chCE7agl conjugates with a c/a ratio of 12 combined high specific activity with good in vitro and in vivo properties. The rapid elimination rate from the blood and the high uptake in the liver of chCE7agl substituted with 15 DOTA ligands were found not to be due to conformational changes of the antibody backbone structure

  3. Isolation, modification, and aldose reductase inhibitory activity of rosmarinic acid derivatives from the roots of Salvia grandifolia.

    Kang, Jie; Tang, Yanbo; Liu, Quan; Guo, Nan; Zhang, Jian; Xiao, Zhiyan; Chen, Ruoyun; Shen, Zhufang

    2016-07-01

    To find aldose reductase inhibitors, two previously unreported compounds, grandifolias H and I, and five known compounds, including rosmarinic acid and rosmarinic acid derivatives, were isolated from the roots of Salvia grandifolia. A series of rosmarinic acid derivatives was obtained from rosmarinic acid using simple synthetic methods. The aldose reductase inhibitory activity of the isolated and synthesized compounds was assessed. Seven of the tested compounds showed moderate aldose reductase inhibition (IC50=0.06-0.30μM). The structure-activity relationship of aldose reductase inhibitory activity of rosmarinic acid derivatives was discussed for the first time. This study provided useful information that will facilitate the development of aldose reductase inhibitors. PMID:27233987

  4. Preparation and adsorption behavior for metal ions and humic acid of chitosan derivatives crosslinked by irradiation

    Introduction: Removing metal ions and humic acid from water in water treatment has attracted much environment and health interests. Adsorbents, derived from a nature polymer, are desired in the viewpoints of environment-conscious technologies. Recently, some nature materials such as chitin, chitosan and their derivatives have been identified as an attractive option due to their distinctive properties. For an insoluble adsorbent based on these polymers to be obtained over a broad pH range, modification through crosslinking is required. Crosslinking agents such as glutaric dialdehyde and ethylene glycol diglycidyl ether are frequently used for modification. However, these crosslinking agents are not preferred because of their physiological toxicity. Radiation-crosslinking without any additive in the fabrication process results in a high-purity product. In a previous work, we applied ionizing radiation to induce the crosslinking of carboxymethylchitosan under highly concentrated paste-like conditions. The aim of this study is to investigate the adsorption behavior of metal ions, humic acid on irradiation-crosslinked carboxymethylchitosan. Experimental: Irradiation of chitosan samples at paste-like state was done with an electron beam. The solubility test of these crosslinked materials were investigated in acidic, alkaline media, and some organic solvents. Swelling and charged characteristic analyses demonstrated typically pH-sensitive properties of these crosslinked materials. Scanning electron microscopic images showed that the crosslinked samples possessed porous morphological structure. The adsorption studies were carried out by the batch method at room temperature. Adsorption of heavy metal ions (such as Cu2+, Cd2+) and humic acid onto crosslinked samples was found to be strongly pH-dependent. Adsorption kinetic studies indicated the rapid removal of metal ions, and humic acid from the aqueous solutions. Also, isothermal adsorption data revealed that Cu2+, Cd2

  5. [Study of pantothenic acid derivatives as cardiac protectors in a model of experimental ischemia and reperfusion of the isolated heart].

    Kumerova, A O; Utno, L Ia; Lipsberga, Z E; Shkestere, I Ia

    1992-04-01

    An isolated heart model with experimental ischemia and reperfusion was used to show effective decrease in lactate, increase in ATP content and prevention of conjugated dienes accumulation in the myocardium by derivatives of pantothenic acid: panthenol (9.0 mg/kg), calcium pantothenate (15.6 mg/kg) and by these ones applied simultaneously as ingredients of perfusate (25 microM) in postischemic period. In that way derivatives of pantothenic acid should be regarded as cardiac protectors. PMID:1391892

  6. Hydrolysis and rearrangement of phthalamic acid derivatives and assessment of their potential as prodrug forms for amines

    Bundgaard, H; Steffansen, B

    1990-01-01

    various other N-alkyl and N-aryl substituted phthalamic acid derivatives were examined with the primary aim of assessing their degradation rate at physiological pH. Whereas the compounds I and II were indeed found to be easily degraded in neutral aqueous solutions, the degradation was not due to....... It is concluded that phthalamic acid derivatives are too stable chemically and enzymatically to be considered as prodrug forms for primary or secondary amines....

  7. Synthesis, characterization and biological evaluation of N-ferrocenylmethyl amino acid benzene carboxamide derivatives and N-ferrocenyl benzoyl amino alkane derivatives as anti-cancer agents.

    Butler, William E.

    2012-01-01

    The aim of this research was to explore the structure-activity relationship (SAR) of ferrocenyl-bioconjugates. A series of N-(ferrocenylmethylamino acid)-fluorinated-benzene carboxamide derivatives and a series of N-(ferrocenyl)-benzoyl-aminoalkane derivatives have been synthesised, structurally characterised and biologically evaluated for their anti-proliferative activity on various cancer cell lines, principally, the (estrogen receptor positive) MCF-7 breast cancer cell line. The anti-c...

  8. Spiculisporic Acids B–D, Three New γ-Butenolide Derivatives from a Sea Urchin-Derived Fungus Aspergillus sp. HDf2

    Xian-Ming Tang; Quan-Ying Feng; Ming-Qiu Yang; Ming-Hui Shen; Tian-Mi Liu; Rong Wang; Xiang-Min Li

    2012-01-01

    Three new γ-butenolide derivatives 1–3, named spiculisporic acids B–D, were isolated from the culture of Aspergillus sp. HDf2, a marine-derived fungus that resides in the sea urchin, Anthocidaris crassispina. The structures of 1–3 were elucidated on the basis of spectroscopic methods, including MS and 2D NMR techniques. Their in vitro cytotoxic activities against two cell lines (SGC-7901, human gastric adenocarcinoma and SPC-A-1, human lung adenocarcinom...

  9. Hypolipidemic effect of pantothenic acid derivatives in mice with hypothalamic obesity induced by aurothioglucose.

    Naruta, E; Buko, V

    2001-10-01

    The hypolipidemic effects of pantothenic acid derivatives (phosphopantothenate, panthenol and pantethine) were studied in mice with hypothalamic obesity. Hypothalamic obesity in mice was induced by single injection of aurothioglucose (300 mg/kg body wt, i.p.). All the tested substances were administered during the last 10 days before decapitation (i.m., of dosage equivalent to 150 mg/kg body wt of phosphopantothenate). The studied substances inhibited the weight gain of the animals with hypothalamic obesity over the last 10 days of the experiment. The treatment with aurothioglucose increased food intake and mean body weight, blood glucose level; insulin, serum total cholesterol, triglyceride, the sum of LDL + VLDL and LDL-cholesterol concentration; triglyceride and cholesterol fractions in the liver; triglyceride and FFA content as well as lipoprotein lipase activity in adipose tissue of experimental mice. The administration of the assay compounds lowered food intake and mean body weight, insulin and glucose levels and decreased the content of triglycerides, total cholesterol and cholesterol esters in serum and adipose tissue as well as raised the activity of lipoprotein lipase in adipose tissue and serum lipolytic activity in obese mice. Among the compounds studied the reverse effect of panthenol was especially pronounced. The mechanism of hypolipidemic effects of pantothenic acid derivatives can be related to the reduced resistance to insulin and activation of lipolysis in serum and adipose tissue. PMID:11817109

  10. Toxicity of Some Cinnamic Acid Derivatives to Common Bean (Phaseolus vulgaris

    Alexandra JITĂREANU

    2011-11-01

    Full Text Available Cinnamic acid derivatives are an important class of biologically active compounds, playing an important role in the plants’ development, but may also present a wide range of actions: antimicrobial, antioxidant, antiinflamatory, antitumoral. The present study investigated the toxicity of ten cinnamic acid derivatives on Phaseolus vulgaris, this being the first step in evaluating their pharmacotoxicological potential (usually, plant toxicity tests are used for ecotoxicity assessment, but they can also provide some useful general information about the toxic potential of a pharmaceutical substance to living organisms. The bean seeds were exposed to three different concentrations of each substance (28.6 μg/cm2, 57.3 μg/cm2, 114.6 μg/cm2. All the tests were conducted in Petri dishes, using an artificial substrate (Whatman filter paper impregnated with the investigated compounds. The analyzed elements were seedling length, root length, percentage of seeds that developed into seedlings, fresh seedling weight and the total polyphenols content. The tested compounds showed phytotoxic effects, inhibiting the growth of the plants and the biosynthesis of polyphenols as compared to the control. The substances with high logP values showed greater phytotoxic potential, but to establish an exact correlation between hydrophobicity and toxicity of the molecules a QSAR analysis must be further done.

  11. Synthesis and Antiproliferative Activity of Some Novel Triazole Derivatives from Dehydroabietic Acid

    Mariano Walter Pertino

    2014-02-01

    Full Text Available Dehydroabietic acid (DHA is a naturally occurring diterpene with different and relevant biological activities. Previous studies have shown that some DHA derivatives display antiproliferative activity. However, the reported compounds did not include triazole derivatives. Starting from DHA (8,11,13-abietatrien-18-oic acid, and its alcohol dehydroabietinol (8,11,13-abietatrien-18-ol, four alkyl esters were prepared. The alkyl terpenes were treated with different aromatic azides to synthesize hybrid compounds using click chemistry. Some 16 new DHA hybrids were thus synthesized and their structures were confirmed by spectroscopic and spectrometric means. The antiproliferative activity of the new compounds was assessed towards human cell lines, namely normal lung fibroblasts (MRC-5, gastric epithelial adenocarcinoma (AGS, lung cancer (SK-MES-1 and bladder carcinoma (J82 cells. Better antiproliferative effect was found for compound 5, with an IC50 of 6.1 μM and selectivity on SK-MES-1 cells. Under the same experimental conditions, the IC50 of etoposide, was 1.83 µM.

  12. Synthesis, spectroscopic characterizations, crystal structures and DFT studies of nalidixic acid carbonyl hydrazones derivatives

    Bergamini, F. R. G.; Ribeiro, M. A.; Lancellotti, M.; Machado, D.; Miranda, P. C. M. L.; Cuin, A.; Formiga, A. L. B.; Corbi, P. P.

    2016-09-01

    This article describes the synthesis and characterization of the 1-ethyl-7-methyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carbohydrazide (hzd) and six carbonyl hydrazones derivatives of the nalidixic with 1H-pyrrol-2-ylmethylidene (hpyrr), 1H-imidazol-2-ylmethylidene (h2imi), pyridin-2-ylmethylidene (h2py), pyridin-3-ylmethylidene (h3py), pyridin-4-ylmethylidene(h4py) and (2-hydroxyphenyl)methylidene (hsali). The carbonyl hydrazones were characterized by elemental and ESI-QTOF-MS analyses, IR and detailed NMR spectroscopic measurements. The 2D NMR experiments allowed the unambiguous assignment of the hydrogen, carbon and nitrogen atoms, which have not been reported for nalidixic acid carbonyl hydrazone derivatives so far. Crystal structures of hzd and the new carbonyl hydrazones h2imi, hpyrr and h3py were determined by X-ray diffraction studies. Although the synthesis of hzd was reported decades ago, the hzd crystal structure have not been reported yet. Geometric optimizations of all the characterized structures were performed with the aid of DFT studies. Despite the fact that the hydrazones with 2-pyridine carboxylic acid (h2py) and salicyl aldehyde (hsali) were already reported by literature, a detailed spectroscopic study followed by DFT studies are also reported for such compounds in this manuscript. Antimicrobial studies of the compounds are also presented.

  13. Synthesis of ino Acid Derived β-Cyclodextrins Used in Chiral Separation by Capillary Electrophoresis

    戴荣继; 佟斌; 魏征; 顾峻岭; 邓玉林; 李明愉; 傅若农

    2004-01-01

    Six new kinds of ino acid derived β-cyclodextrins were synthesized to improve their water solubility and chiral separation properties. They are heptakis{2,6-di-O-[3-L-(1-isopropyl carboxyl methyl ino)-2-hydroxy propyl]}-β-cyclodextrin (i.e. L-Val-β-CD), heptakis{2,6-di-O-[3-L-(1-benzyl carboxyl methyl ino)-2-hydroxy propyl]}-β-cyclodextrin (i.e. L-Phe-β-CD), heptakis{2,6-di-O-[3-(D, L-1-benzyl carboxyl methyl ino)-2-hydroxy propyl]}-β-cyclodextrin (i.e. D,L-Phe-β-CD), heptakis{2,6-di-O-[3-(L-1-hydroxymethyl carboxyl methyl ino)-2-hydroxy propyl]}-β-cyclodextrin (i.e. L-Ser-β-CD), heptakis{2,6-di-O-[3-(L-1-carboxylmethyl carboxyl methyl ino)- 2-hydroxy propyl]}-β-cyclodextrin (i.e. L-Asp-β-CD), heptakis{2,6-di-O-[3-(L-2-carboxyl tetrethylene ino)-2-hydroxy propyl]}-β-cyclodextrin (i.e. L-Pro-β-CD). Their chemical structures were certified using FTIR and 1H NMR. Except for L-Phe-β-CD and D,L-Phe-β-CD, that are in soluble in water, the other ino acid derived β-CDs all have good water solubility. D,L-tyrosine and promethazine were baselinely separated by L-Val-β-CD in capillary electrophoresis.

  14. 1,2,3-Triazole-Substituted Oleanolic Acid Derivatives: Synthesis and Antiproliferative Activity

    Guillermo Schmeda-Hirschmann

    2013-07-01

    Full Text Available Hybrid compounds are relevant products when searching for structure-activity relationships of natural products. Starting from the naturally occurring triterpene oleanolic acid, alkyl esters were prepared and treated with different aromatic azides using click chemistry to produce hybrid compounds. Some 18 new oleanolic acid derivatives were synthesized and the structures were confirmed by spectroscopic and spectrometric means. The antiproliferative activity of the new derivatives was evaluated towards normal lung fibroblasts (MRC-5, gastric epithelial adenocarcinoma (AGS, promyelocytic leukemia (HL-60, lung cancer (SK-MES-1 and bladder carcinoma (J82 cells. The alkyne esters 1 and 3 showed activity on all cell lines but without selectivity (19.6–23.1 μM and 14.1–56.2 μM, respectively, their respective methyl esters were inactive. Compounds with a benzene and p-anisole attached to the triazole ring, showed no antiproliferative effect. Introduction of a chlorine atom into the benzene ring (compound 9 elicited a selective effect against AGS cells (IC50 value: 8.9 μM. The activity was lost when the COOH function at C-28 was methylated. Better antiproliferative effect was found for compounds 11 and 15 bearing a p-toluenesulphonyl group, with values in the range of 10.8–47.1 μM and 11.5–22.2 μM, respectively. The effect, however, was not associated with selectivity.

  15. Synthesis and Application of Phenyl Nitrone Derivatives as Acidic and Microbial Corrosion Inhibitors

    Shijun Chen

    2015-01-01

    Full Text Available Nitrone has drawn great attention due to its wide applications as a 1,3-dipole in heterocyclic compounds synthesis and the bioactivities. With the special structure, nitrone can also be used as ligand in inorganic chemistry. Based on the current research, the nitrones are anticipated to be effective inhibitors against acidic and microbial corrosion. The aim of this work is to investigate the inhibitory action of nitrones. In this work, a series of phenyl nitrone derivatives (PN was synthesized and used as acidic and microbial corrosion inhibitors. The results indicate that several compounds show moderate to high inhibition efficiency (IE in 3% HCl. Accompanied with HMTA or BOZ, the IEs greatly increase, and the highest efficiency of 98.5% was obtained by using PN4 + BOZ. Investigation of the antibacterial activity against oilfield microorganism shows that the nitrone derivatives can inhibit SRB, IB, and TGB with moderate to high efficiency under 1,000 mg/L, which makes them potential to be used as bifunctional oilfield chemicals.

  16. Preparation and evaluation of 177Lu-DOTA-Bz-RGD dimer and 177Lu-DOTA-Bz-PEG4-RGD dimer

    177Lu-DOTA-Bz-RGD dimer and 177Lu-DOTA-Bz-PEG4-RGD dimer were pre- pared, and the effect of PEG4 on labeling conditions and in vitro stability as well as pharma-cokinetic properties and biodistribution in normal mice for the radiolebeled compounds was compared. The results of TLC and HPLC show that the labeling yield of two radiolabeled compounds was more than 95% under optimal conditions (pH 4.0 and pH 6.0, respectively, reacting at 100 degree C for 15-20 min). The two radiolabeled compounds show pretty good stability in saline. HPLC analyses and lgPow values revealed that introducing of PEG4 increased the lipophilic character of radiolabeled compounds, but had no significant changes on pharmacokinetic properties and biodistribution in normal mice. (authors)

  17. Rapid formation of β-allyl substituted isotetronic acid derivatives via Claisen rearrangement using a microfludic device

    Xia Ping Ma; Zhi Ming Li; Quan Rui Wang

    2011-01-01

    The thermal Claisen rearrangement of O-allyl substituted isotetronic acids 1 was successfully carried out within a glass microreactor operated with temperature at 150 ℃ and a flow rate of 1 mL/h. The strategy provides an efficient alternative way to β-allyl substituted isotetronic acid derivatives 2 in high yields with much accelerated reaction speed.

  18. Study of application properties of novel trisazo hetero bi-functional reactive dyes based on j-acid derivatives for cotton

    Three novel trisazo hetero bi-functional reactive dyes based on J-acid derivatives were prepared using the diazonium salt of [4-(4-sulphophenylazo-)-2,5-dimethylazobenzene-2-sulphonic acid] and a hetero bi-functional coupling component, derived from 1-hydroxy-6-aminonapthalene-3-sulphonic acid (J-acid), 1-hydroxy-6- methylaminonapthalene-3-sulphonic acid (methyl J-acid), and 1-hydroxy-6-aminonaphthalene-3,5-disulphonic acid (sulpho J-acid). On balance, the dye derived from sulpho J-acid displayed the most attractive set of technical properties, building up and fixing more efficiently than those derived from J-acid and methyl J-acid. In addition, the sulpho J-acid based dye offered better migration and, therefore, level dyeing and ease of wash off. (author)

  19. Amino acid esters substituted phosphorylated emtricitabine and didanosine derivatives as antiviral and anticancer agents.

    Sekhar, Kuruva Chandra; Janardhan, Avilala; Kumar, Yellapu Nanda; Narasimha, Golla; Raju, Chamarthi Naga; Ghosh, S K

    2014-07-01

    Owing to the promising antiviral activity of amino acid ester-substituted phosphorylated nucleosides in the present study, a series of phosphorylated derivatives of emtricitabine and didanosine substituted with bioactive amino acid esters at P-atom were synthesized. Initially, molecular docking studies were screened to predict their molecular interactions with hemagglutinin-neuraminidase protein of Newcastle disease virus and E2 protein of human papillomavirus. The title compounds were screened for their antiviral ability against Newcastle disease virus (NDV) by their in ovo study in embryonated chicken eggs. Compounds 5g and 9c exposed well mode of interactions with HN protein and also exhibited potential growth of NDV inhibition. The remaining compounds exhibited better growth of NDV inhibition than their parent molecules, i.e., emtricitabine (FTC) and didanosine (ddI). In addition, the in vitro anticancer activity of all the title compounds were screenedagainst HeLa cell lines at 10 and 100 μg/mL concentrations. The compounds 5g and 9c showed an effective anticancer activity than that of the remaining title compounds with IC50 values of 40 and 60 μg/mL, respectively. The present in silico and in ovo antiviral and in vitro anticancer results of the title compounds are suggesting that the amino acid ester-substituted phosphorylated FTC and ddI derivatives, especially 5g and 9c, can be used as NDV inhibitors and anticancer agents for the control and management of viral diseases with cancerous condition. PMID:24789416

  20. Protective effects of a dimeric derivative of ferulic acid in animal models of Alzheimer's disease.

    Jung, Jun-Sub; Yan, Ji-Jing; Li, Hong-Mei; Sultan, Md Tipu; Yu, Jaehoon; Lee, Hee-Sul; Shin, Kye-Jung; Song, Dong-Keun

    2016-07-01

    Ferulic acid is a compound with potent anti-oxidant and anti-inflammatory activities. We previously reported the protective effects of ferulic acid administration against two animal models of Alzheimer's disease (AD): intracerebroventricular (i.c.v.) injection of Aß1-42 in mice and APP/PS1 mutant transgenic mice. In this study using the same AD animal models, we examined the effect of KMS4001, one of dimeric derivatives of ferulic acid. Intragastric pretreatment of mice with KMS4001 (30mg/kg/day) for 5 days significantly attenuated the Aß1-42 (i.c.v.)-induced memory impairment both in passive avoidance test and in Y-maze test. APP/PS1 mutant transgenic mice at KMS4001 doses of 3 and 30mg/kg/day via drinking water showed the significantly enhanced novel-object recognition memory at both 1.5 and 3 months after the start of KMS4001 treatment. Treatment of APP/PS1 mutant transgenic mice with KMS4001 for 3 months at the doses of 3 and 30mg/kg/day markedly decreased Aβ1-40 and Aβ1-42 levels in the frontal cortex. The KMS4001 dose-response relationships for Aβ decrease and for improvement in novel-object recognition test corresponded to each other. Taken together, these results suggest that KMS4001 could be an effective drug candidate against AD. PMID:27118174