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Sample records for regioisomeric ring-substituted fluorophenethylamines

  1. Pharmacological examination of trifluoromethyl ring-substituted methcathinone analogs

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    Cozzi, Nicholas V.; Brandt, Simon D.; Daley, Paul F.; Partilla, John S.; Rothman, Richard B.; Tulzer, Andreas; Sitte, Harald H.; Baumann, Michael H.

    2013-01-01

    Cathinones are a class of drugs used to treat various medical conditions including depression, obesity, substance abuse, and muscle spasms. Some “designer” cathinones, such as methcathinone, mephedrone, and methylone, are used nonclinically for their stimulant or entactogenic properties. Given the recent rise in nonmedical use of designer cathinones, we aimed to improve understanding of cathinone pharmacology by investigating analogs of methcathinone with a CF3 substituent at the 2-, 3-, or 4-position of the phenyl ring (TFMAPs). We compared the TFMAPs with methcathinone for effects on monoamine uptake transporter function in vitro and in vivo, and for effects on locomotor activity in rats. At the serotonin transporter (SERT), 3-TFMAP and 4–TFMAP were 10-fold more potent than methcathinone as uptake inhibitors and as releasing agents, but 2-TFMAP was both a weak uptake inhibitor and releaser. At the norepinephrine and dopamine transporters (NET and DAT), all TFMAP isomers were less potent than methcathinone as uptake inhibitors and releasers. In vivo, 4-TFMAP released 5-HT, but not dopamine, in rat nucleus accumbens and did not affect locomotor activity, whereas methcathinone increased both 5-HT and dopamine and produced locomotor stimulation. These experiments reveal that TFMAPs are substrates for the monoamine transporters and that phenyl ring substitution at the 3- or 4-position increases potency at SERT but decreases potency at NET and DAT, resulting in selectivity for SERT. The TFMAPs might have a therapeutic value for a variety of medical and psychiatric conditions and may have lower abuse liability compared to methcathinone due to their decreased DAT activity. PMID:23178523

  2. Binding of ring-substituted indole-3-acetic acids to human serum albumin.

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    Soskić, Milan; Magnus, Volker

    2007-07-01

    The plant hormone, indole-3-acetic acid (IAA), and its ring-substituted derivatives have recently attracted attention as promising pro-drugs in cancer therapy. Here we present relative binding constants to human serum albumin for IAA and 34 of its derivatives, as obtained using the immobilized protein bound to a support suitable for high-performance liquid chromatography. We also report their octanol-water partition coefficients (logK(ow)) computed from retention data on a C(18) coated silica gel column. A four-parameter QSPR (quantitative structure-property relationships) model, based on physico-chemical properties, is put forward, which accounts for more than 96% of the variations in the binding affinities of these compounds. The model confirms the importance of lipophilicity as a global parameter governing interaction with serum albumin, but also assigns significant roles to parameters specifically related to the molecular topology of ring-substituted IAAs. Bulky substituents at ring-position 6 increase affinity, those at position 2 obstruct binding, while no steric effects were noted at other ring-positions. Electron-withdrawing substituents at position 5 enhance binding, but have no obvious effect at other ring positions.

  3. Investigating the spectrum of biological activity of ring-substituted salicylanilides and carbamoylphenylcarbamates.

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    Otevrel, Jan; Mandelova, Zuzana; Pesko, Matus; Guo, Jiahui; Kralova, Katarina; Sersen, Frantisek; Vejsova, Marcela; Kalinowski, Danuta S; Kovacevic, Zaklina; Coffey, Aidan; Csollei, Jozef; Richardson, Des R; Jampilek, Josef

    2010-11-10

    In this study, a series of twelve ring-substituted salicylanilides and carbamoylphenylcarbamates were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET) in spinach (Spinacia oleracea L.) chloroplasts. Moreover, their site of action in the photosynthetic apparatus was determined. Primary in vitro screening of the synthesized compounds was also performed against mycobacterial, bacterial and fungal strains. Several compounds showed biological activity comparable with or higher than the standards 3-(3,4-dichlorophenyl)-1,1-dimethylurea, isoniazid, penicillin G, ciprofloxacin or fluconazole. The most active compounds showed minimal anti-proliferative activity against human cells in culture, indicating they would have low cytotoxicity. For all compounds, the relationships between lipophilicity and the chemical structure are discussed.

  4. Investigating the Spectrum of Biological Activity of Ring-Substituted Salicylanilides and Carbamoylphenylcarbamates

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    Josef Jampilek

    2010-11-01

    Full Text Available In this study, a series of twelve ring-substituted salicylanilides and carbamoylphenylcarbamates were prepared and characterized. The compounds were analyzed using RP-HPLC to determine lipophilicity. They were tested for their activity related to the inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. Moreover, their site of action in the photosynthetic apparatus was determined. Primary in vitro screening of the synthesized compounds was also performed against mycobacterial, bacterial and fungal strains. Several compounds showed biological activity comparable with or higher than the standards 3-(3,4-dichlorophenyl-1,1-dimethylurea, isoniazid, penicillin G, ciprofloxacin or fluconazole. The most active compounds showed minimal anti-proliferative activity against human cells in culture, indicating they would have low cytotoxicity. For all compounds, the relationships between lipophilicity and the chemical structure are discussed.

  5. Preparation and Biological Properties of Ring-Substituted Naphthalene-1-Carboxanilides

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    Tomas Gonec

    2014-07-01

    Full Text Available In this study, a series of twenty-two ring-substituted naphthalene-1-carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized carboxanilides was performed against Mycobacterium avium subsp. paratuberculosis. N-(2-Methoxyphenylnaphthalene-1-carboxamide, N-(3-methoxy-phenylnaphthalene-1-carboxamide, N-(3-methylphenylnaphthalene-1-carboxamide, N-(4-methylphenylnaphthalene-1-carboxamide and N-(3-fluorophenylnaphthalene-1-carboxamide showed against M. avium subsp. paratuberculosis two-fold higher activity than rifampicin and three-fold higher activity than ciprofloxacin. The most effective antimycobacterial compounds demonstrated insignificant toxicity against the human monocytic leukemia THP-1 cell line. The testing of biological activity of the compounds was completed with the study of photosynthetic electron transport (PET inhibition in isolated spinach (Spinacia oleracea L. chloroplasts. The PET-inhibiting activity expressed by IC50 value of the most active compound N-[4-(trifluoromethylphenyl]naphthalene-1-carboxamide was 59 μmol/L. The structure-activity relationships are discussed.

  6. Antibacterial and Herbicidal Activity of Ring-Substituted 2-Hydroxynaphthalene-1-carboxanilides

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    Katarina Kralova

    2013-08-01

    Full Text Available In this study, a series of twenty-two ring-substituted 2-hydroxynaphthalene-1‑carboxanilides were prepared and characterized. Primary in vitro screening of the synthesized compounds was performed against Staphylococcus aureus, three methicillin-resistant S. aureus strains, Mycobacterium marinum, M. kasasii, M. smegmatis. and M. avium paratuberculosis. The compounds were also tested for their activity related to inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. 2-Hydroxy-N-phenylnaphthalene-1-carboxanilide and 2-hydroxy-N-(3-trifluoromethylphenylnaphthalene-1-carboxamide (IC50 = 29 µmol/L were the most active PET inhibitors. Some of tested compounds showed the antibacterial and antimycobacterial activity against the tested strains comparable or higher than the standards ampicillin or isoniazid. Thus, for example, 2-hydroxy-N-(3-nitrophenylnaphthalene-1-carboxamide showed MIC = 26.0 µmol/L against methicillin-resistant S. aureus and MIC = 51.9 µmol/L against M. marinum, or 2-hydroxy-N-phenylnaphthalene-1-carboxamide demonstrated MIC = 15.2 µmol/L against M. kansasii. The structure-activity relationships for all compounds are discussed.

  7. Antibacterial and Herbicidal Activity of Ring-Substituted 3-Hydroxynaphthalene-2-carboxanilides

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    Katarina Kralova

    2013-07-01

    Full Text Available In this study, a series of twenty-two ring-substituted 3-hydroxy-N-phenylnaphthalene-2-carboxanilides were prepared and characterized. The compounds were tested for their activity related to inhibition of photosynthetic electron transport (PET in spinach (Spinacia oleracea L. chloroplasts. Primary in vitro screening of the synthesized compounds was also performed against four Staphylococcus strains and against two mycobacterial species. 3-Hydroxy-N-(2-methoxyphenylnaphthalene-2-carboxamide showed high biological activity (MIC = 55.0 µmol/L against S. aureus as well as methicillin-resistant strains. N-(2-Fluorophenyl-3-hydroxynaphthalene-2-carboxamide showed higher activity (MIC = 28.4 µmol/L against M. marinum than the standard isoniazid and 3-hydroxy-N-(4-nitrophenylnaphthalene-2-carboxamide expressed higher activity (MIC = 13.0 µmol/L against M. kansasii than the standard isoniazid. Cytotoxicity assay of effective antimicrobial compounds was performed using the human monocytic leukemia THP-1 cell line. The PET-inhibiting activity expressed by IC50 value of the most active compound 3-hydroxy-N-(3-nitrophenylnaphthalene-2-carboxamide was 16.9 μmol/L. The structure-activity relationships of all compounds are discussed.

  8. A click approach to novel D-ring-substituted 16α-triazolylestrone derivatives and characterization of their antiproliferative properties.

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    Judit Molnár

    Full Text Available A simple and efficient synthesis of novel, D-ring substituted estrone derivatives containing a 16α-triazolyl moiety is described. Two epimeric azido alcohols (16α-azido-17α-hydroxy and 16α-azido-17β-hydroxy of estra-1,3,5(10-triene-3-methyl ether were prepared, followed by copper(I-catalyzed azide-alkyne cycloaddition with various terminal alkynes. The steroidal triazoles were obtained in high yields and their activities against three human cancer cell lines (HeLa, MCF7 and A431 were screened. The most effective analogs were submitted to additional experiments in order to characterize their antiproliferative properties. As evidenced by flow cytometry, the selected steroids induced a disturbance in the HeLa cell cycle in a concentration- and exposure-dependent manner, through an increase of the hypodiploid population (subG1 and a cell cycle arrest in the G2/M phase. A noncancerous human fibroblast cell line (MRC5 was used to determine the selectivities of these compounds. Fluorescent microscopy after Hoechst 33258 - propidium iodide (HOPI double staining revealed nuclear condensation and disturbed cell membrane integrity. The enhanced activities of caspase-3 and caspase-9 without activation of caspase-8 in the treated cells indicated the activation of the intrinsic pathway of apoptosis. The levels of cell cycle regulators (CDK1, cyclin B1/B2 and cdc25B were decreased and the ratio Bax/Bcl-2 was increased 24 h after the treatment of HeLa cells (determined at an mRNA level by means of an RT-PCR technique. Under the same conditions, two agents elicited substantially increased degrees of phosphorylation of stathmin, as evidenced by Western blotting. The presented results demonstrate that these steroids can be regarded as appropriate structural scaffolds for the design and synthesis of further steroid analogs as innovative drug candidates with good efficacy.

  9. Mapping the regioisomeric distribution of fatty acids in triacylglycerols by hybrid mass spectrometry.

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    Nagy, Kornél; Sandoz, Laurence; Destaillats, Frédéric; Schafer, Olivier

    2013-01-01

    This study describes the use of hybrid mass spectrometry for the mapping, identification, and semi-quantitation of triacylglycerol regioisomers in fats and oils. The identification was performed based on the accurate mass and fragmentation pattern obtained by data-dependent fragmentation. Quantitation was based on the high-resolution ion chromatograms, and relative proportion of sn-1(3)/sn-2 regioisomers was calculated based on generalized fragmentation models and the relative intensities observed in the product ion spectra. The key performance features of the developed method are inter-batch mass accuracy < 1 ppm (n = 10); lower limit of detection (triggering threshold) 0.1 μg/ml (equivalent to 0.2 weight % in oil); lower limit of quantitation 0.2 μg/ml (equivalent to 0.4 weight % in oil); peak area precision 6.5% at 2 μg/ml concentration and 15% at 0.2 μM concentration; inter-batch precision of fragment intensities < 1% (n = 10) independent of the investigated concentration; and averaged accuracy using the generic calibration 3.8% in the 1-10 μg/ml range and varies between 1-23% depending on analytes. Inter-esterified fat, beef tallow, pork lard, and butter fat samples were used to show how well regioisomeric distribution of palmitic acid can be captured by this method.

  10. Time-resolved kinetic study of the electron-transfer reactions between ring-substituted cumyloxyl radicals and alkylferrocenes. Evidence for an inner-sphere mechanism.

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    Bietti, Massimo; DiLabio, Gino A; Lanzalunga, Osvaldo; Salamone, Michela

    2011-03-18

    A time-resolved kinetic study of the reactions of ring-substituted cumyloxyl radicals (4-X-CumO(•): X = OMe, t-Bu, Me, Cl, CF(3)) with methylferrocenes (Me(n)Fc: n = 2, 8, 10) has been carried out in acetonitrile solution. Evidence for an electron transfer (ET) process has been obtained for all radicals and an increase in reactivity has been observed on decreasing the oxidation potential of the ferrocene donor and on going from electron-releasing to electron-withdrawing ring substituents. Computations predict the formation of strongly bound π-stacked 4-X-CumO(•)/DcMFc complexes, characterized by intracomplex π-π distances around 4 Å. These findings point toward a (nonbonded) inner-sphere ET mechanism for the reactions of the 4-X-CumO(•)/Me(n)Fc couples.

  11. And yet they glow: thiazole based push-pull fluorophores containing nitro groups and the influence of regioisomerism

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    Habenicht, Stefanie H.; Siegmann, Michael; Kupfer, Stephan; Kübel, Joachim; Weiß, Dieter; Cherek, Doreen; Möller, Uwe; Dietzek, Benjamin; Gräfe, Stefanie; Beckert, Rainer

    2015-06-01

    Reported is a study on the influence of regioisomerism on the photophysical properties in 4-hydroxy-1,3-thiazole-based push-pull-chromophores/fluorophores to evaluate the molecular structure-property relationship as a basic foundation for future design strategies concerning this class of dyes. Surprisingly, the nitro groups used as acceptors do not act as a fluorescence quencher, instead the derivatives synthesized exhibit quantum yields of 37-40%. Two 4-ethoxy-1,3-thiazole derivatives which differ only in the positioning of their electron donating (methoxy) and electron withdrawing (nitro) groups have been synthesized and examined in terms of their photophysical properties, i.e. UV/Vis absorption and fluorescence emission spectra. Additionally, quantum chemical calculations have been performed to unravel the underlying fundamental transitions and to explain the experimental results.

  12. Identification and quantification of regioisomeric cholesteryl linoleate hydroperoxides in oxidized human low density lipoprotein and high density lipoprotein.

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    Kenar, J A; Havrilla, C M; Porter, N A; Guyton, J R; Brown, S A; Klemp, K F; Selinger, E

    1996-06-01

    Oxidation of human LDL is implicated as an initiator of atherosclerosis. Isolated low density lipoprotein (LDL) and high density lipoprotein (HDL2) were exposed to aqueous radicals generated from the thermolabile azo compound 2,2'-azobis(2-amidinopropane) dihydrochloride. The primary nonpolar lipid products formed from the autoxidation of LDL and HDL were the regioisomeric cholesteryl linoleate hydroperoxides. In LDL oxidations, 9- and 13-hydroperoxides with trans,cis conjugated diene were formed as the major oxidation products if endogenous alpha-tocopheral was present in the LDL. After extended oxidation of LDL, at the time when endogenous alpha-tocopherol was consumed, the two trans,cis conjugated diene hydroperoxides began to disappear and the 9- and 13-hydroperoxides with trans,trans conjugated diene appeared. At very long oxidation times, none of the primary products, the conjugated diene hydroperoxides, were present. In HDL2, which has only very low levels of antioxidants, both the 9- and 13-hydroperoxides with trans,cis conjugated diene and the 9- and 13-hydroperoxides with trans,trans conjugated diene were formed at early stages of oxidation. The corresponding alcohols were also formed in the HDL2 oxidations. A mechanistic hypothesis consistent with these observations is presented.

  13. Anti-leishmanial and structure-activity relationship of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives

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    Asunción Burguete

    2008-12-01

    Full Text Available A series of ring substituted 3-phenyl-1-(1,4-di-N-oxide quinoxalin-2-yl-2-propen-1-one derivatives were synthesized and tested for in vitro leishmanicidal activity against amastigotes of Leishmania amazonensis in axenical cultures and murine infected macrophages. Structure-activity relationships demonstrated the importance of a radical methoxy at position R3', R4' and R5'. (2E-3-(3,4,5-trimethoxy-phenyl-1-(3,6,7-trimethyl-1,4-dioxy-quinoxalin-2-yl-propenone was the most active. Cytotoxicity on macrophages revealed that this product was almost six times more active than toxic.

  14. 3,3'-Diindolylmethane (DIM) and its ring-substituted halogenated analogs (ring-DIMs) induce differential mechanisms of survival and death in androgen-dependent and -independent prostate cancer cells.

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    Goldberg, Alexander A; Draz, Hossam; Montes-Grajales, Diana; Olivero-Verbél, Jesus; Safe, Stephen H; Sanderson, J Thomas

    2015-05-01

    We recently reported that novel ring-substituted analogs of 3,3'-diindolylmethane (ring-DIMs) induce apoptosis and necrosis in androgen-dependent and -independent prostate cancer cells. In this paper, we have focused on the mechanism(s) associated with ring-DIM-mediated cell death, and on identifying the specific intracellular target(s) of these compounds. The 4,4'- and 7,7'-dichloroDIMs and 4,4'- and 7,7'-dibromoDIMs induced the death of LNCaP, C42B and DU145 prostate cancer cells, but not that of immortalized normal human prostate epithelial (RWPE-1) cells. Ring-DIMs caused the early loss of mitochondrial membrane potential (MMP) and decreased mitochondrial ATP generation in prostate cancer cells. Cyclosporin A, an inhibitor of the mitochondrial permeability transition pore, inhibited ring-DIM-mediated cell death, and salubrinal, an inhibitor of ER stress, inhibited cell death mediated only by 4,4'-dihaloDIMs. We found that although salubrinal did not inhibit the onset of ER stress, it prevented 4,4'-dibromoDIM mediated loss of MMP. Salubrinal potentiated cell death in response to 7,7'-dihaloDIMs and DIM, and this effect concurred with increased loss of MMP. Using in silico 3-D docking affinity analysis, we identified Ca2+/calmodulin-dependent kinase II (CaMKII) as a potential direct target for the most toxic ring-DIM, 4,4'-dibromoDIM. An inhibitor of CaMKII, KN93, but not its inactive analog KN92, abrogated cell death mediated by 4,4'-dibromoDIM. The ring-DIMs induced ER stress and autophagy, but these processes were not necessary for ring-DIM-mediated cell death. Inhibition of autophagy with bafilomycin A1, 3-methyladenine or by LC3B gene silencing sensitized LNCaP and C42B, but not ATG5-deficient DU145 cells to ring-DIM- and DIM-mediated cell death. We propose that autophagy induced by the ring-DIMs and DIM has a cytoprotective function in prostate cancer cells.

  15. Regioisomerism of triacylglycerols in lard, tallow, yolk, chicken skin, palm oil, palm olein, palm stearin, and a transesterified blend of palm stearin and coconut oil analyzed by tandem mass spectrometry.

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    Kallio, H; Yli-Jokipii, K; Kurvinen, J P; Sjövall, O; Tahvonen, R

    2001-07-01

    Triacylglycerols (TAG) of lard, tallow, egg yolk, chicken skin, palm oil, palm olein, palm stearin, and a transesterified blend of palm stearin and coconut oil (82:18) were investigated by chemical ionization and collision-induced dissociation tandem mass spectrometry. Accurate molecular level information of the regioisomeric structures of individual TAGs was achieved. When existing in a TAG molecule of lard, palmitic acid occupied 90-100% of the sn-2 position. Within the major fatty acid combinations in tallow TAGs, the secondary position sn-2 was preferentially occupied in the decreasing order by oleoyl > palmitoyl > stearoyl residues, the order in saturated TAGs being myristoyl > stearoyl = palmitoyl. TAGs in egg yolk were more asymmetric than in chicken skin, with linoleic acid highly specifically attached in the yolk sn-2 carbon. Nearly 50% of yolk TAGs contained 52 carbon atoms with two or three double bonds. Linoleic, oleic, and palmitic acids were in the sn-2 location in decreasing quantities in palm oil and its fractions. Triacylglycerols of equal molecular weight behaved similarly in the fractionation process. Randomization of the parent oil TAGs was seen in the transesterified oil. The tandem mass spectrometric analysis applied provided detailed information of the distribution of fatty acids in individual combinations in TAGs.

  16. Second generation benzofuranone ring substituted noscapine analogs: synthesis and biological evaluation.

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    Mishra, Ram Chandra; Karna, Prasanthi; Gundala, Sushma Reddy; Pannu, Vaishali; Stanton, Richard A; Gupta, Kamlesh Kumar; Robinson, M Hope; Lopus, Manu; Wilson, Leslie; Henary, Maged; Aneja, Ritu

    2011-07-15

    Microtubules, composed of α/β tubulin heterodimers, represent a validated target for cancer chemotherapy. Thus, tubulin- and microtubule-binding antimitotic drugs such as taxanes and vincas are widely employed for the chemotherapeutic management of various malignancies. Although quite successful in the clinic, these drugs are associated with severe toxicity and drug resistance problems. Noscapinoids represent an emerging class of microtubule-modulating anticancer agents based upon the parent molecule noscapine, a naturally occurring non-toxic cough-suppressant opium alkaloid. Here we report in silico molecular modeling, chemical synthesis and biological evaluation of novel analogs derived by modification at position-7 of the benzofuranone ring system of noscapine. The synthesized analogs were evaluated for their tubulin polymerization activity and their biological activity was examined by their antiproliferative potential using representative cancer cell lines from varying tissue-origin [A549 (lung), CEM (lymphoma), MIA PaCa-2 (pancreatic), MCF-7 (breast) and PC-3 (prostate)]. Cell-cycle studies were performed to explore their ability to halt the cell-cycle and induce subsequent apoptosis. The varying biological activity of these analogs that differ in the nature and bulk of substituent at position-7 was rationalized utilizing predictive in silico molecular modeling.

  17. Stable ion study of benzo[a]pyrene (BaP) derivatives: 7,8-dihydro-BaP, 9,10-dihydro-BaP and its 6-halo derivatives, 1- and 3-methoxy-9,10-dihydro-BaP-7(8H)-one, as well as the proximate carcinogen BaP 7,8-dihydrodiol and its dibenzoate, combined with a comparative DNA binding study of regioisomeric (1-, 4-, 2-) pyrenylcarbinols.

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    Okazaki, Takao; Laali, Kenneth K; Zajc, Barbara; Lakshman, Mahesh K; Kumar, Subodh; Baird, William M; Dashwood, Wan-Mohaiza

    2003-05-01

    A stable ion study of a series of BaP derivatives is reported. 7,8-Dihydro-BaP 1 gives a persistent bay-region benzyliclike carbocation which shows extensive charge delocalization into the pyrene moiety. In contrast, a "benzylic" carbocation can not be generated from 9,10-dihydro-BaP 2. Introduction of bulky substituents at peri C-6 of 9,10-dihydro-BaP (as in 4 and 5) prevents side reactions (dimerization) to the extent that the initially formed carbocation undergoes rearrangement to generate the corresponding bay-region "benzylic" carbocation as a persistent species. Introduction of methoxy substituents into the 1- or 3-positions of 9,10-dihydro-BaP-7(8H)-one (6,7) increases its electrophilic reactivity to the extent that stable carboxonium-arenium dications are produced in FSO3H-SO2ClF. A detailed NMR study (at 500 MHz) of the resulting mono- and dications is reported, and charge delocalization mode (as well as conformational aspects) are addressed. Other oxidized derivatives of BaP such as the 7,8-dihydrodiol 9 and the 7,8-dihydrodibenzoate 8 are not suitable models for stable ion study because of competing O-protonation (and elimination). Energies for various possible arenium ions and regioisomeric "benzylic" cations were computed by the DFT method at the B3LYP/6-31G(d)//B3LYP/6-31G(d) level or by AM1 for comparison with the experimental results. These findings provide further evidence in support of the stability sequence: 1-pyrenyl > 4-pyrenyl > 2-pyrenyl in alpha-pyrene-substituted carbocations as models for the intermediates arising from BaP-epoxide ring opening. In an effort to provide a parallel, a series of alpha-pyrenylcarbinols were subjected to a DNA binding study using human MCF-7 cells. The results/trends are discussed and compared with the stable ion data.

  18. The Effect of Ring Substitution Position on the Structural Conformation of Mercaptobenzoic Acid Self-Assembled Monolayers on Au(111)

    Energy Technology Data Exchange (ETDEWEB)

    Lee, J; Willey, T; Nilsson, J; Terminello, L; De Yoreo, J; van Buuren, T

    2006-04-12

    Near edge X-ray absorption fine structure (NEX-AFS) spectroscopy, photoemission spectroscopy (PES) and contact angle measurements have been used to examine the structure and bonding of self-assembled monolayers (SAMs) prepared on Au(111) from the positional isomers of mercaptobenzoic acid (MBA). The isomer of MBA and solvent chosen in SAM preparation has considerable bearing upon film morphology. Carbon K-edge NEXAFS measurements indicate that the monomers of 2-, 3- and 4-MBA have well-defined orientations within their respective SAMs. Monomers of 3- and 4-MBA assume an upright orientation on the Au substrates in monolayers prepared using an acetic acid in ethanol solvent. The aryl ring and carboxyl group of these molecules are tilted from the surface normal by a colatitudal angle of {approx} 30{sup o}. Preparation of 4-MBA SAMs using pure ethanol solvent, a more traditional means of synthesis, had no appreciable effect upon the monomer orientation. Nonetheless, S(2p) PES measurements illustrate that it results in extensive bilayer formation via carboxyl group hydrogen-bonding between 4-MBA monomers. In 2-MBA monolayers prepared using acetic acid/ethanol solvent, the monomers adopt a more prostrate orientation on the Au substrates, in which the aryl ring and carboxyl group of the molecules are tilted {approx} 50{sup o} from the surface normal. This configuration is consistent with an interaction between both the mercaptan sulfur and carboxyl group of 2-MBA with the underlying substrate. S(2p) and C(1s) PES experiments provide supporting evidence for a bidentate interaction between 2-MBA and Au(111).

  19. Phenyl ring-substituted lobelane analogs: inhibition of [³H]dopamine uptake at the vesicular monoamine transporter-2.

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    Nickell, Justin R; Zheng, Guangrong; Deaciuc, Agripina G; Crooks, Peter A; Dwoskin, Linda P

    2011-03-01

    Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [³H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [³H]dopamine (DA) uptake into isolated synaptic vesicles and determined the mechanism of inhibition. Introduction of aromatic substituents in lobelane maintained analog affinity for the [³H]DTBZ binding site on VMAT2 and inhibitory potency in the [³H]DA uptake assay assessing VMAT2 function. The most potent (K(i) = 13-16 nM) analogs in the series included para-methoxyphenyl nor-lobelane (GZ-252B), para-methoxyphenyl lobelane (GZ-252C), and 2,4-dichlorphenyl lobelane (GZ-260C). Affinity of the analogs for the [³H]DTBZ binding site did not correlate with inhibitory potency in the [³H]DA uptake assay. It is noteworthy that the N-benzylindole-, biphenyl-, and indole-bearing meso-analogs 2,6-bis[2-(1-benzyl-1H-indole-3-yl)ethyl]-1-methylpiperidine hemifumarate (AV-1-292C), 2,6-bis(2-(biphenyl-4-yl)ethyl)piperidine hydrochloride (GZ-272B), and 2,6-bis[2-(1H-indole-3-yl)ethyl]-1-methylpiperidine monofumarate (AV-1-294), respectively] inhibited VMAT2 function (K(i) = 73, 127, and 2130 nM, respectively), yet had little to no affinity for the [³H]DTBZ binding site. These results suggest that the analogs interact at an alternate site to DTBZ on VMAT2. Kinetic analyses of [³H]DA uptake revealed a competitive mechanism for 2,6-bis(2-(4-methoxyphenyl)ethyl)piperidine hydrochloride (GZ-252B), 2,6-bis(2-(4-methoxyphenyl)ethyl)-1-methylpiperidine hydrochloride (GZ-252C), 2,6-bis(2-(2,4-dichlorophenyl)ethyl)piperidine hydrochloride (GZ-260C), and GZ-272B. Similar to methamphetamine, these analogs released [³H]DA from the vesicles, but with higher potency. In contrast to methamphetamine, these analogs had higher potency (>100-fold) at VMAT2 than DAT, predicting low abuse liability. Thus, modification of the lobelane molecule affords potent, selective inhibitors of VMAT2 function and reveals two distinct pharmacological targets on VMAT2.

  20. Phenyl Ring-Substituted Lobelane Analogs: Inhibition of [3H]Dopamine Uptake at the Vesicular Monoamine Transporter-2

    Science.gov (United States)

    Nickell, Justin R.; Zheng, Guangrong; Deaciuc, Agripina G.; Crooks, Peter A.

    2011-01-01

    Lobeline attenuates the behavioral effects of methamphetamine via inhibition of the vesicular monoamine transporter (VMAT2). To increase selectivity for VMAT2, chemically defunctionalized lobeline analogs, including lobelane, were designed to eliminate nicotinic acetylcholine receptor affinity. The current study evaluated the ability of lobelane analogs to inhibit [3H]dihydrotetrabenazine (DTBZ) binding to VMAT2 and [3H]dopamine (DA) uptake into isolated synaptic vesicles and determined the mechanism of inhibition. Introduction of aromatic substituents in lobelane maintained analog affinity for the [3H]DTBZ binding site on VMAT2 and inhibitory potency in the [3H]DA uptake assay assessing VMAT2 function. The most potent (Ki = 13–16 nM) analogs in the series included para-methoxyphenyl nor-lobelane (GZ-252B), para-methoxyphenyl lobelane (GZ-252C), and 2,4-dichlorphenyl lobelane (GZ-260C). Affinity of the analogs for the [3H]DTBZ binding site did not correlate with inhibitory potency in the [3H]DA uptake assay. It is noteworthy that the N-benzylindole-, biphenyl-, and indole-bearing meso-analogs 2,6-bis[2-(1-benzyl-1H-indole-3-yl)ethyl]-1-methylpiperidine hemifumarate (AV-1-292C), 2,6-bis(2-(biphenyl-4-yl)ethyl)piperidine hydrochloride (GZ-272B), and 2,6-bis[2-(1H-indole-3-yl)ethyl]-1-methylpiperidine monofumarate (AV-1-294), respectively] inhibited VMAT2 function (Ki = 73, 127, and 2130 nM, respectively), yet had little to no affinity for the [3H]DTBZ binding site. These results suggest that the analogs interact at an alternate site to DTBZ on VMAT2. Kinetic analyses of [3H]DA uptake revealed a competitive mechanism for 2,6-bis(2-(4-methoxyphenyl)ethyl)piperidine hydrochloride (GZ-252B), 2,6-bis(2-(4-methoxyphenyl)ethyl)-1-methylpiperidine hydrochloride (GZ-252C), 2,6-bis(2-(2,4-dichlorophenyl)ethyl)piperidine hydrochloride (GZ-260C), and GZ-272B. Similar to methamphetamine, these analogs released [3H]DA from the vesicles, but with higher potency. In contrast to methamphetamine, these analogs had higher potency (>100-fold) at VMAT2 than DAT, predicting low abuse liability. Thus, modification of the lobelane molecule affords potent, selective inhibitors of VMAT2 function and reveals two distinct pharmacological targets on VMAT2. PMID:20876747

  1. 13C-n.m.r. spectra of acrylophenone (1-phenylprop-2-en-1-one) and ring-substituted acrylophenones

    NARCIS (Netherlands)

    Visser, R.; Dahmen, E.A.M.F.

    1978-01-01

    13C-n.m.r. chemical shifts of 10 acrylophenones (1-substituted phenylprop-2-en-1-ones) are reported. The additivity parameters for the substituent effect of the acryloyl group in the aromatic ring and of the benzoyl group in ethylene were calculated. Comparison of ethene chemical shifts in chalcones

  2. Regioisomeric SCFA attachment to hexosamines separates metabolic flux from cytotoxicity and MUC1 suppression.

    Science.gov (United States)

    Aich, Udayanath; Campbell, Christopher T; Elmouelhi, Noha; Weier, Christopher A; Sampathkumar, S-Gopalan; Choi, Sean S; Yarema, Kevin J

    2008-04-18

    Chemical biology studies, exemplified by metabolic glycoengineering experiments that employ short chain fatty acid (SCFA)-hexosamine monosaccharide hybrid molecules, often suffer from off-target effects. Here we demonstrate that systematic structure-activity relationship (SAR) studies can deconvolute multiple biological activities of SCFA-hexosamine analogues by demonstrating that triacylated monosaccharides, including both n-butyrate- and acetate-modified ManNAc analogues, had dramatically different activities depending on whether the free hydroxyl group was at the C1 or C6 position. The C1-OH (hemiacetal) analogues enhanced growth inhibition in MDA-MB-231 human breast cancer cells and suppressed expression of MUC1, which are attractive properties for an anticancer agent. By contrast, C6-OH analogues supported high metabolic flux into the sialic acid pathway with negligible growth inhibition or toxicity, which are desirable properties for glycan labeling in healthy cells. Importantly, these SAR were general, applying to other hexosamines ( e.g., GlcNAc) and non-natural sugar "scaffolds" ( e.g., ManNLev). From a practical standpoint, the ability to separate toxicity from flux will facilitate the use of MOE analogues for cancer treatment and glycomics applications, respectively. Mechanistically, these findings overturn the premise that the bioactivities of SCFA-monosaccharide hybrid molecules result from their hydrolysis products ( e.g., n-butyrate, which acts as a histone deacetylase inhibitor, and ManNAc, which activates sialic acid biosynthesis); instead the SAR establish that inherent properties of partially acylated hexosamines supersede the cellular responses supported by either the acyl or monosaccharide moieties.

  3. 5-hydroxytryptamine- and dopamine-releasing effects of ring-substituted amphetamines on rat brain: a comparative study using in vivo microdialysis.

    Science.gov (United States)

    Matsumoto, T; Maeno, Y; Kato, H; Seko-Nakamura, Y; Monma-Ohtaki, J; Ishiba, A; Nagao, M; Aoki, Y

    2014-08-01

    Using in vivo microdialysis, a comparative study was conducted to examine the effects of amphetamine-related compounds (methamphetamine, MAP; 3,4-methylenedioxymethamphetamine, MDMA; p-methoxyamphetamine, PMA; p-methoxymethamphetamine, PMMA; 4-methylthioamphetamine, 4-MTA; 3,4,5-trimethoxyamphetamine, TMA; 2,5-dimethoxy-4-iodoamphetamine, DOI) on extracellular levels of serotonin (5-HT) and dopamine (DA). Dialysates were assayed using HPLC equipped with electrochemical detector following i.p. administration with each drug at a dose of 5 mg/kg. MAP was found to drastically and rapidly increase 5-HT and DA levels (870% and 1460%, respectively). PMA, PMMA, and 4-MTA slightly increased DA levels (150-290%) but remarkably increased 5-HT levels (540-900%). In contrast, TMA and DOI caused no detectable changes in levels of both monoamines. We observed that the potent DA-releasing action of MAP was remarkably decreased by introduction of methoxy or methylthio group at the para position (MAP vs. PMMA or 4-MTA), but introduction of two additional adjacent methoxy groups into PMA totally abolished its 5-HT-/DA-releasing action (PMA vs. TMA). In addition, para-mono-substituted compounds inhibited both monoamine oxidase (MAO) enzymes more strongly than other compounds; PMA and 4-MTA exhibited submicromolar IC50 values for MAO-A. On the other hand, TMA scarcely affected the activity of both MAO enzymes as well as extracellular levels of 5-HT and DA. In this comparative study, MDMA, PMA, and 4-MTA functioned similar to PMMA, a typical empathogen; these findings therefore could be helpful in clarifying the psychopharmacological properties of amphetamine-related, empathogenic designer drugs.

  4. Synthesis and Resolution of Ring-substituted phenylalanines%苯环取代苯丙氨酸的合成及拆分

    Institute of Scientific and Technical Information of China (English)

    梁远军; 刘克良; 于文胜; 赵玉芬

    2001-01-01

    Seven racemic aromatic ring modified phenylalanines wer e sy nthesized using aniline derivatives as raw materials. The amino acids were resol ved with α--chymotrypsin or subtilisin. D-and L-amino acids were separ ated from each other. The chemical structures of the amino acids were characteri zed by IR, 1 HNMR, EA and optical rotation. The procedure mentioned here coul d be scaled up for producing the amino acids.%以苯胺类化合物为起始原料,经重氮化、丙烯酸加成、氨解 等反应合成了7种消旋苯环取代苯丙氨酸类氨基酸,并采用α-糜蛋白酶或枯草杆菌蛋白酶 对所有氨基酸进行了拆分,其结构分别通过红外光谱、核磁共振、元素分析、熔点、旋光等 分析得到确证。该法可以较大规模合成此类氨基酸。

  5. Synthesis and In Vitro Antiproliferative Activity of Novel Phenyl Ring-Substituted 5-Alkyl-12(H)-quino[3,4-b][1,4]benzothiazine Derivatives.

    Science.gov (United States)

    Zięba, Andrzej; Latocha, Małgorzata; Sochanik, Aleksander; Nycz, Anna; Kuśmierz, Dariusz

    2016-11-04

    A novel series of tetracyclic quinobenzothiazine derivatives was synthetized. Compounds containing a substituent (hydroxyl, methyl, phenyl, piperidyl, or piperazinyl) in positions 9 and 11 were obtained by cyclization of suitable 4-aminoquinolinium-3-thiolates. Quinobenzothiazine 10-O-substituted derivatives were obtained by alkylating the hydroxyl group in position 10 of the parent (quinobenzothiazine) system. Antiproliferative activity of the synthesized compounds was studied using cultured neoplastic cells (MDA-MB-231, SNB-19, and C-32 cell lines). Four selected compounds were investigated in more detail for cytotoxicity and antiproliferative effect. Transcriptional activity of genes regulating cell cycle (TP53), apoptosis (BAX, BCL-2), as well as proliferation (H3) were assessed. Finally, the ability of the selected compounds to bind DNA was checked in the presence of ethidium bromide.

  6. Synthesis and In Vitro Antiproliferative Activity of Novel Phenyl Ring-Substituted 5-Alkyl-12(H-quino[3,4-b][1,4]benzothiazine Derivatives

    Directory of Open Access Journals (Sweden)

    Andrzej Zięba

    2016-11-01

    Full Text Available A novel series of tetracyclic quinobenzothiazine derivatives was synthetized. Compounds containing a substituent (hydroxyl, methyl, phenyl, piperidyl, or piperazinyl in positions 9 and 11 were obtained by cyclization of suitable 4-aminoquinolinium-3-thiolates. Quinobenzothiazine 10-O-substituted derivatives were obtained by alkylating the hydroxyl group in position 10 of the parent (quinobenzothiazine system. Antiproliferative activity of the synthesized compounds was studied using cultured neoplastic cells (MDA-MB-231, SNB-19, and C-32 cell lines. Four selected compounds were investigated in more detail for cytotoxicity and antiproliferative effect. Transcriptional activity of genes regulating cell cycle (TP53, apoptosis (BAX, BCL-2, as well as proliferation (H3 were assessed. Finally, the ability of the selected compounds to bind DNA was checked in the presence of ethidium bromide.

  7. Regioisomeric effects on the electronic features of indenothiophene-bridged D-π-A'-A DSSC sensitizers.

    Science.gov (United States)

    Chou, Shu-Hua; Tsai, Chih-Hung; Wu, Chung-Chih; Kumar, Dhirendra; Wong, Ken-Tsung

    2014-12-08

    Two D-π-A'-A regioisomers (A-IDT-D and D-IDT-A) featuring 4,4'-di-p-tolyl-4 H-indeno[1,2-b]-thiophene as a π linker (π) between the diarylamino donor (D) and the pyrimidine-cyanoacrylic acid acceptor (A'-A) have been successfully synthesized and characterized as efficient sensitizers for the dye-sensitized solar cells (DSSCs). The different arrangements of the D and A'-A blocks on the unsymmetrical indenothiophene (IDT) core render the dipole of IDT being along (A-IDT-D) or opposite (D-IDT-A) to the direction of intramolecular (donor-to-acceptor) charge transfer, and thus induce variations in the physical properties. The experimental observations correlated well with the theoretical analyses, clearly revealing the trade-off between the molar extinction coefficient (ε) and the S0 →S1 transition energy. As a result, a superior ε value was observed for D-IDT-A, whereas a bathochromic shift in the absorption occurred in A-IDT-D. The larger ε value of D-IDT-A together with its more favorable energy level relative to TiO2 led to a higher power conversion efficiency of 7.41 % for the D-IDT-A-based DSSC, retaining approximately 95 % of the N719-based DSSC efficiency. This work manifests the clear structure-property relationship for the case of donor and acceptor components being connected by an unsymmetrical π linker and provides insights for molecular engineering of organic sensitizers.

  8. Genistein Derivatives Regioisomerically Substituted at 7-O- and 4′-O- Have Different Effect on the Cell Cycle

    Directory of Open Access Journals (Sweden)

    A. Byczek

    2013-01-01

    Full Text Available Our previous studies on antiproliferative properties of genistein derivatives substituted at C7 hydroxyl group of the ring A revealed some compounds with antimitotic properties. The aim of this work was to synthesize their analogues substituted at the 4′-position of the ring B in genistein and to define their antiproliferative mechanism of action in selected cancer cell lines in vitro. C4′-substituted glycoconjugates were obtained in a three-step procedure: (1 alkylation with an ω-bromoester; (2 deacylation; (3 Ferrier-type rearrangement glycosylation with acylated glycals. Biological effects including antiproliferative effects of the compounds, cell cycle, DNA lesions (ATM activation, H2A.X phosphorylation, and micronuclei formation, and autophagy were studied in human cancer cell lines. Some of the tested derivatives potently inhibited cell proliferation. The presence of a substituent at the 4′-position of the ring B in genistein correlated to a p53-independent G1 cell-cycle arrest. The derivatives substituted at C4′ did not induce DNA lesions and appeared to be nongenotoxic. The tested compounds induced autophagy and caused remarkable decrease of cell volume.

  9. Design, synthesis, and structure-affinity relationships of regioisomeric N-benzyl alkyl ether piperazine derivatives as sigma-1 receptor ligands.

    Science.gov (United States)

    Moussa, Iman A; Banister, Samuel D; Beinat, Corinne; Giboureau, Nicolas; Reynolds, Aaron J; Kassiou, Michael

    2010-08-26

    A series of N-(benzofuran-2-ylmethyl)-N'-benzylpiperazines bearing alkyl or fluoroalkyl aryl ethers were synthesized and evaluated at various central nervous system receptors. Examination of in vitro sigma1 {[3H]+-pentazocine} and sigma2 ([3H]DTG) receptor binding profiles of piperazines 11-13 and 25-36 revealed several highly potent and sigma1 selective ligands, notably, N-(benzofuran-2-ylmethyl)-N'-(4'-methoxybenzyl)piperazine (13, Ki=2.7 nM, sigma2/sigma1=38) and N-(benzofuran-2-ylmethyl)-N'-(4'-(2''-fluoroethoxy)benzyl)piperazine (30, Ki=2.6 nM, sigma2/sigma1=187). Structural features for optimal sigma1 receptor affinity and selectivity over the sigma2 receptor were identified. On the basis of its favorable log D value, 13 was selected as a candidate for the development of a sigma1 receptor positron emission tomography radiotracer. [11C]13 showed high uptake in the brain and other sigma receptor-rich organs of a Papio hamadryas baboon. The in vivo evaluation of [11C]13 indicates that this radiotracer is a suitable candidate for imaging the sigma1 receptor in neurodegenerative processes.

  10. Structural elucidation of biologically active neomycin N-octyl derivatives in a regioisomeric mixture by means of liquid chromatography/ion trap time-of-flight mass spectrometry.

    Science.gov (United States)

    Giera, Martin; de Vlieger, Jon S B; Lingeman, Henk; Irth, Hubertus; Niessen, Wilfried M A

    2010-05-30

    Structural elucidation of six regioisomers of mono-N-octyl derivatized neomycin is achieved using MS(n) (up to n = 4) on an ion trap time-of-flight (IT-TOF) instrument equipped with electrospray ionization. The mixture of six derivatized neomycin analogues was generated by reductive amination in a shotgun synthetic approach. In parallel to the liquid chromatography/mass spectrometry (LC/MS) detection, the antibacterial activity of the neomycin regioisomers was tested by post-column addition of buffer and bacterial inocula, subsequent microfractionation of the resulting mixture, incubation, and finally a chemiluminescence-based bioactivity measurement based on the production of bacterial ATP. The MS-based high-resolution screening approach described can be applied in medicinal chemistry to help in designing and producing new antibiotic substances, which is particularly challenging due to the high functionality of most antibiotic substances, therefore requiring advanced (hyphenated) separation and detection techniques for compound mixtures.

  11. Pharmacophore modeling and conformational analysis in the gas phase and in aqueous solution of regioisomeric melatonin analogs. A theoretical and experimental study

    Science.gov (United States)

    Mendoza-Figueroa, Humberto; Martínez-Gudiño, Gelacio; Villanueva-Luna, Jorge E.; Trujillo-Serrato, Joel J.; Morales-Ríos, Martha S.

    2017-04-01

    In this work, 2-(N-acylaminoalkyl)indoles 1a-1d, that incorporate a pMeOBn group at the 3-position of the indole ring were virtual screened as potential melatoninergic ligands by analog-based design study using pharmacophore modeling. Pharmacophore models for melatoninergic agonist and antagonist activity were developed in order to identify the molecular constraints that define the geometric relationship among chemical features in each model. The best hypothesis consisted of six features for agonists and eight features for antagonists. The models suggest that the agonists and antagonists can share the same 3D arrangement for the six common pharmacophoric elements identified: two hydrogen bond acceptors (HBA), one hydrogen bond donor (HBD), one hydrophobic area (H), and two aromatic rings (AR). The extra hydrofobic interaction might be used as criterion for identified the pharmacological antagonist profile. Based on the pharmacophore fit, it was found that structures 1c and 1d show a good structural overlay that meets the requirements for the antagonistic pharmacophore hypothesis. Molecular modeling studies using the PCM solvation model predicted that the most stable conformers of 1a-1d match the antagonist pharmacophore hypothesis in contrast to those in the gas phase. Structures 1a-1c were synthesized only but the activities were not tested.

  12. EFSA Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids (CEF); Scientific Opinion on Flavouring Group Evaluation 22, Revision 1 (FGE.22Rev1): Ring substituted phenolic substances from chemical groups 21 and 25

    DEFF Research Database (Denmark)

    Larsen, John Christian; Nørby, Karin Kristiane; Beltoft, Vibe Meister;

    The Panel on Food Contact Materials, Enzymes, Flavourings and Processing Aids of the European Food Safety Authority was requested to evaluate 28 flavouring substances in the Flavouring Group Evaluation 22, Revision 1, using the Procedure in Commission Regulation (EC) No 1565/2000. The substance 3...... concerns at their levels of dietary intake, estimated on the basis of the MSDI approach. Adequate specifications for the materials of commerce are available for all 27 flavouring substances evaluated through the Procedure....

  13. Crystal structures of three anhydrous salts of the Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU with the ring-substituted benzoic acid analogues 4-aminobenzoic acid, 3,5-dinitrobenzoic acid and 3,5-dinitrosalicylic acid

    Directory of Open Access Journals (Sweden)

    Graham Smith

    2016-03-01

    Full Text Available The anhydrous salts of the Lewis base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU with 4-aminobenzoic acid [1-aza-8-azoniabicyclo[5.4.0]undec-7-ene 4-aminobenzoate, C9H17N2+·C7H6NO2− (I], 3,5-dinitrobenzoic acid [1-aza-8-azoniabicyclo[5.4.0]undec-7-ene 3,5-dinitrobenzoate, C9H17N2+·C7H3N2O6−, (II] and 3,5-dinitrosalicylic acid (DNSA [1-aza-8-azoniabicyclo[5.4.0]undec-7-ene 2-hydroxy-3,5-dinitrobenzoate, C9H17N2+·C7H3N2O7−, (III] have been determined and their hydrogen-bonded structures are described. In both (II and (III, the DBU cations have a common disorder in three of the C atoms of the six-membered ring moieties [site-occupancy factors (SOF = 0.735 (3/0.265 (3 and 0.686 (4/0.314 (4, respectively], while in (III, there is additional rotational disorder in the DNSA anion, giving two sites (SOF = 0.72/0.28, values fixed for the phenol group. In the crystals of (I and (III, the cation–anion pairs are linked through a primary N—H...Ocarboxyl hydrogen bond [2.665 (2 and 2.869 (3 Å, respectively]. In (II, the ion pairs are linked through an asymmetric three-centre R12(4, N—H...O,O′ chelate association. In (I, structure extension is through amine N—H...Ocarboxyl hydrogen bonds between the PABA anions, giving a three-dimensional structure. The crystal structures of (II and (III are very similar, the cation–anion pairs being associated only through weak C—H...O hydrogen bonds, giving in both overall two-dimensional layered structures lying parallel to (001. No π–π ring associations are present in any of the structures.

  14. Effect of Bronsted Acids and Bases, and Lewis Acid (Sn(2+)) on the Regiochemistry of the Reaction of Amines with Trifluoromethyl-β-diketones: Reaction of 3-Aminopyrrole to Selectively Produce Regioisomeric 1H-Pyrrolo[3,2-b]pyridines.

    Science.gov (United States)

    De Rosa, Michael; Arnold, David; Hartline, Douglas; Truong, Linda; Verner, Roman; Wang, Tianwei; Westin, Christian

    2015-12-18

    Reaction of 3-aminopyrrole (as its salt) with trifluoromethyl-β-diketones gave γ-1H-pyrrolo[3,2-b]pyridines via reaction at the less reactive carbonyl group. The trifluoromethyl group increased the electrophilicity of the adjacent carbonyl group and decreased the basicity of the hydroxyl group of the CF3 amino alcohol formed. This amino alcohol was formed faster, but its subsequent dehydration to the β-enaminone was slow resulting in the preferential formation of the γ-regioisomer. Reaction of 4,4,4-trifluoro-1-phenyl-1,3-butadione with 3-aminopyrrole was carried out using a series of 6 amine buffers. Yields of the α-1H-pyrrolo[3,2-b]pyridine increased as the pKa of the amine buffer decreased. Surprisingly the yield went down at higher pKas. There was a change in mechanism as the reaction mixture became more basic. With strong amines trifluoromethyl-β-diketones were present mainly or completely as the enolate. Under reductive conditions (3-nitropyrrole/Sn/AcOH/trifluoromethyl-β-diketone) the α-1H-pyrrolo[3,2-b]pyridine was the major product as a result of Lewis acid catalysis by Sn(2+). Similar α-regiochemistry was observed when the reaction of the 3-aminopyrrole salt with trifluoromethyl-β-diketones was carried out in the presence of base and tin(II) acetate.

  15. Microwave mediated synthesis of spiro-(indoline-isoxazolidines): mechanistic study and biological activity evaluation

    DEFF Research Database (Denmark)

    Raunak, R.; Kumar, Vineet; Mukherjee, Shubhasish;

    2005-01-01

    Regioisomeric spiro-(indoline-isoxazolidines) have been synthesized in moderate yields by the cycloaddition reaction between ethyl (3-indolylidene)acetate and various substituted α,N-diphenylnitrones, using environmentally benign microwave technology. A novel concerted reaction mechanism is descr...

  16. Analysis and protease-catalysed synthesis of sucrose alkanoate regioisomers

    DEFF Research Database (Denmark)

    Lie, Aleksander

    2014-01-01

    The aims of the presented research were to develop quantifiable methods for reversed-phase high-performance liquid chromatography analysis of sucrose alkanoate regioisomers and to investigate the activity and regioisomeric distribution in the biocatalytic esterification of sucrose with vinyl...... formulations. Differences in regioisomeric distribution after 48 hours appeared partly to stem from differences in overall reaction rates, as the different reaction conditions resulted in similar distributions after different reaction times. The esterification of sucrose with vinyl laurate with no protein...

  17. Convenient one-step synthesis of 5-carboxy-seminaphthofluoresceins

    DEFF Research Database (Denmark)

    Hammershøj, Peter; Thyhaug, Erling; Harris, Pernille

    2017-01-01

    The one-step synthesis and characterization of a series of regioisomerically pure 5-carboxy-seminaphthofluoresceins (5-carboxy-SNAFLs) is reported. The optical properties were determined in aqueous buffer at around biological pH, and highly pH sensitive, large Stokes-shift fluorophores with emiss......The one-step synthesis and characterization of a series of regioisomerically pure 5-carboxy-seminaphthofluoresceins (5-carboxy-SNAFLs) is reported. The optical properties were determined in aqueous buffer at around biological pH, and highly pH sensitive, large Stokes-shift fluorophores...

  18. Dinuclear barium(II) complexes based on a calix[4]arene scaffold as catalysts of acyl transfer

    NARCIS (Netherlands)

    Cacciapaglia, Roberta; Casnati, Alessandro; Di Stefano, Stefano; Mandolini, Luigi; Paolemili, Daniele; Reinhoudt, David; Sartori, A.; Ungaro, Rocco

    2004-01-01

    Two novel regioisomeric calix[4]arene derivatives (2 and 3), decorated with two aza[18]crown-6 units at vicinal (1,2) or diagonal (1,3) positions of the upper rim, were synthesized. The catalytic activities of their dinuclear Ba2+ complexes were investigated in the ethanolysis of esters 8-11,

  19. Regioselective Allene Hydrosilylation Catalyzed by NHC Complexes of Nickel and Palladium

    Science.gov (United States)

    Miller, Zachary D.; Li, Wei; Belderrain, Tomás R.; Montgomery, John

    2013-01-01

    Regioselective methods for allene hydrosilylation have been developed, with regioselectivity being governed primarily by choice of metal. Alkenylsilanes are produced via nickel catalysis with larger N-heterocyclic carbene ligands, and allylsilanes are produced via palladium catalysis with smaller N-heterocyclic carbene ligands. These complementary methods allow either regioisomeric product to be obtained with exceptional regiocontrol. PMID:24079389

  20. Synthesis and GC-MS analysis of a series of homologs and regioisomers of 3,4-methylenedioxypyrovalerone (MDPV).

    Science.gov (United States)

    Abiedalla, Younis F Hamad; Abdel-Hay, Karim; DeRuiter, Jack; Clark, C Randall

    2012-11-30

    A series of ten homologous and regioisomeric aminoketones related to the designer synthetic cathinone derivative MDPV were evaluated in this study. These compounds were prepared from a common precursor chemical, piperonal (3,4-methylenedioxybenzaldehyde). These aminoketones show major peaks in their mass spectra corresponding to the regioisomeric and homologous immonium cation fragments from the loss of the methylenedioxybenzoyl radical species. All ten compounds in this study show equivalent EI MS fragments for the 3,4-methylenedioxybenzoyl fragments (m/z 149) and the methylenedioxybenzene fragment at m/z 121. The m/z 149 results from ionization of the carbonyl oxygen followed by an alpha-cleavage fragmentation. The loss of CO from this ion yields the m/z 121 fragments common to all spectra. The regioisomeric aminoketones yield equivalent mass spectra including mass equivalent regioisomeric immonium cation base peaks. A subset of these compounds has the same molecular weight and almost identical mass spectra to that of the designer drug MDPV. An evaluation of the effects of homologation on gas chromatographic retention showed that addition of a methylene (CH(2)) in the nitrogen-containing ring increases retention more than the equivalent group added to the alkyl side-chain. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  1. Ratios of regioisomers of minor acylglycerols less polar than triricinolein in castor oil estimated by mass spectrometry (Abstract)

    Science.gov (United States)

    The ratios of regioisomers of triacylglycerols (TAG) have been estimated by mass spectrometry using the fact that the neutral loss of fatty acid (FA) from the sn-2 position is energetically less favored in comparison with that from sn-1,3 positions. However regioisomeric TAG standards were needed fo...

  2. Convenient one-step synthesis of 5-carboxy-seminaphthofluoresceins

    DEFF Research Database (Denmark)

    Hammershøj, Peter; Thyhaug, Erling; Harris, Pernille

    2017-01-01

    The one-step synthesis and characterization of a series of regioisomerically pure 5-carboxy-seminaphthofluoresceins (5-carboxy-SNAFLs) is reported. The optical properties were determined in aqueous buffer at around biological pH, and highly pH sensitive, large Stokes-shift fluorophores with emiss...

  3. Proline Catalyzed Asymmetric Aldol Reaction between Methyl Ketones and 1-Aryl-2,2,2-trifluoroethanones

    Institute of Scientific and Technical Information of China (English)

    QIU Li-Hua; SHEN Zong-Xuan; SHI Chang-Qing; LIU Yan-Hua; ZHANG Ya-Wen

    2005-01-01

    Direct asymmetric aldol addition of methyl ketones to 2,2,2-trifluoro-1-phenylethanone and its ring-substituted derivatives was achieved using L-proline as a chiral promoter. Various optically active β-trifluoromethyl-β-hydroxy ketones were obtained in almost quantitative yields with moderate enantioselectivities up to 64 % ee.

  4. Dipolar Dyes with a Pyrrolo[2,3-b]quinoxaline Skeleton Containing a Cyano Group and a Bridged Tertiary Amino Group: Synthesis, Solvatofluorochromism, and Bioimaging.

    Science.gov (United States)

    Łukasiewicz, Łukasz G; Deperasińska, Irena; Poronik, Yevgen M; Jun, Yong Woong; Banasiewicz, Marzena; Kozankiewicz, Bolesław; Ahn, Kyo Han; Gryko, Daniel T

    2016-06-01

    Two strongly polarized dipolar chromophores possessing a cyclic tertiary amino group at one terminus of the molecule and a CN group at the opposite terminus were designed and synthesized. Their rigid skeleton contains the rarely studied pyrrolo[2,3-b]quinoxaline ring system. The photophysical properties of these regioisomeric dyes were different owing to differing π conjugation between the CN group and the electron-donor moiety. These dipolar molecules showed very intense emission, strong solvatofluorochromism, and sufficient two-photon brightness for bioimaging. One of these regioisomeric dyes, namely, 11-carbonitrile-2,3,4,5,6,7-hexahydro-1H-3a,8,13,13b-tetraazabenzo[b]cyclohepta[1,2,3-jk]fluorene, was successfully utilized in two-photon imaging of mouse organ tissues and showed distinct tissue morphology with high resolution.

  5. [BMIM][PF(6)] promotes the synthesis of halohydrin esters from diols using potassium halides.

    Science.gov (United States)

    Oromí-Farrús, Mireia; Eras, Jordi; Villorbina, Gemma; Torres, Mercè; Llopis-Mestre, Veronica; Welton, Tom; Canela, Ramon

    2008-10-01

    Haloesterification of diverse diols with various carboxylic acids was achieved using potassium halides (KX) as the only halide source in ionic liquids. The best yield was obtained in [BMIM][PF(6)] when 1,2-octanediol, palmitic acid and KBr were used. This yield was 85% and the regioisomer with the bromine in primary position was present in a 75:25 ratio. The regioisomeric ratio could be improved using either KCl or some phenylcarboxylic acids. [BMIM][PF(6)] acts as both reaction media and catalyst of the reaction. To the best of our knowledge, this type of combined reaction using an ionic liquid is unprecedented. The other solvents tested did not lead either to the same yield or to the same regioisomeric ratio.

  6. Soluble Polymer-Supported Synthesis of Pyrazoles via 1,3-Dipolar Cycloaddition Strategy

    Institute of Scientific and Technical Information of China (English)

    LIN,Xu-Feng(林旭锋); WANG,Yan-Guang(王彦广); DING,Han-Feng(丁寒锋)

    2004-01-01

    Rapid parallel liquid-phase synthesis of pyrazoles has first been developed.The 1,3-dipolar cycloaddition between nitrilimines generated in situ and soluble polymer-supported alkynyl or alkenyl dipolarophiles in parallel one-pot fashion gave the corresponding PEG-supported regioisomeric pyrazoles or regiospecific pyrazolines.The latter was assuredly oxidated by DDQ to PEG-supported regiospecific pyrazoles.Cleavage from the support under mild conditions afforded pyrazoles in good yields and high purity.

  7. Synthesis of a des-B-Ring Bryostatin Analogue Leads to an Unexpected Ring Expansion of the Bryolactone Core

    OpenAIRE

    Kraft, Matthew B.; Poudel, Yam B.; Kedei, Noemi; Lewin, Nancy E.; Peach, Megan L.; Blumberg, Peter M.; Keck, Gary E.

    2014-01-01

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biolog...

  8. Carotenoid Antenna Binding and Function in Retinal Proteins

    Science.gov (United States)

    2012-08-13

    REPORT Carotenoid antenna binding and function in retinal proteins 14. ABSTRACT 16. SECURITY CLASSIFICATION OF: Xanthorhodopsin, a proton pump from the...eubacterium Salinibacter ruber, is a unique dual chromophore system that contains, in addition to retinal, the carotenoid salinixanthin as a light... carotenoid ring near the retinal ring. Substitution of the small glycine with bulky tryptophan in this site eliminates binding. The second factor is the 4

  9. Efficient Route to Deuterated Aromatics by the Deamination of Anilines.

    Science.gov (United States)

    Burglova, Kristyna; Okorochenkov, Sergei; Hlavac, Jan

    2016-07-15

    One-step replacement of NH2 groups in ring-substituted anilines by deuterium is reported. Approaches comprising both solid-phase and solution-phase syntheses can be used on a large variety of substrates. The method uses diazotization in a mixture of water and either dichloromethane or chloroform, which serve as a source of hydrogen. This protocol can be used as a general method for fast and easy incorporation of deuterium into an aromatic system using deuterated chloroform.

  10. Dual stereoselectivity in the dialkylzinc reaction using (-)-beta-pinene derived amino alcohol chiral auxiliaries.

    Science.gov (United States)

    Binder, Caitlin M; Bautista, April; Zaidlewicz, Marek; Krzemiński, Marek P; Oliver, Allen; Singaram, Bakthan

    2009-03-20

    (+)-Nopinone, prepared from naturally occurring (-)-beta-pinene, was converted to the two regioisomeric amino alcohols 3-MAP and 2-MAP in very good yield and excellent isomeric purity. Amino alcohol 3-MAP was synthesized by converting (+)-nopinone to the corresponding alpha-ketooxime. This was reduced to the primary amino alcohol and was converted to the morpholino group through a simple substitution reaction. 3-MAP was characterized by X-ray crystallography, which displayed the rigidity of the pinane framework. Amino alcohol 2-MAP was prepared from its trans isomer 2, which in turn was synthesized via hydroboration/oxidation of the morpholine enamine of (+)-nopinone. Two-dimensional NMR was used to characterize amino alcohol 2-MAP, and NOE was used to confirm its relative stereochemistry. These amino alcohols were employed as chiral auxiliaries in the addition of diethylzinc to benzaldehyde to obtain near-quantitative asymmetric induction in the products. The use of 3-MAP yielded (S)-phenylpropanol in 99% ee, and its regioisomer 2-MAP gave the opposite enantiomer, (R)-phenylpropanol, also in 99% ee. Other aromatic, aliphatic, and alpha,beta-unsaturated aldehydes were implemented in this method, affording secondary alcohols in high yield and enantiomeric excess. Amino alcohols 2-MAP and 3-MAP were also found to be useful in the dimethylzinc addition reaction, both catalyzing the addition to benzaldehyde with nearly quantitative ee. Regioisomeric amino alcohols 2-MAP and 3-MAP, even though they were prepared from one enantiomer of nopinone, provide antipodal enantiofacial selectivity in the dialkylzinc addition reaction. This circumvents the necessity to synthesize amino alcohols derived from (-)-nopinone, which in turn requires the unnatural (+)-beta-pinene. Possible mechanistic insights are offered to explain the dual stereoselectivity observed in the diethylzinc addition reaction involving regioisomeric, pseudo-enantiomeric amino alcohols 3-MAP and 2-MAP.

  11. Applicability of non-linear versus linear fractional abundance calibration plots for the quantitative determination of triacylglycerol regioisomers by tandem mass spectrometry.

    Science.gov (United States)

    Ramaley, Louis; Herrera, Lisandra Cubero; Melanson, Jeremy E

    2013-06-15

    Regioisomeric analysis of triacylglycerols is important in understanding lipid biochemistry and the involvement of lipids in disease and nutrition. The use of calibration plots employing fractional abundances provides a simple and rapid method for such analyses. These plots are believed to be linear, but evidence exists for non-linearity. The behavior of such plots needs to be understood to allow for proper interpretation of regioisomeric data. Solutions of five regioisomer pairs were prepared from pure standards and used to construct calibration plots using triple-stage tandem mass spectrometry (MS(3) ) with electrospray ionization (ESIMS(3) ) and cationization by lithium ions. The data were taken by direct infusion with an AB SCIEX QTRAP 2000 QqLIT mass spectrometer. Non-linear calibration plots were observed for the four isomer pairs containing the polyunsaturated eicosapentaenoic (20:5) and docosahexaenoic (22:6) acids paired with palmitic acid (16:0) or myristic acid (14:0), while the pair including palmitic and stearic (18:0) acids provided a linear plot. A non-linear model was developed for these plots and then verified experimentally. The fractional abundance calibration plots used in regioisomeric analysis of triacylglycerols are intrinsically non-linear, but may appear linear if the scatter in data points obscures the curvature, if the curvature is slight, or if the response factors for the two isomers in the regioisomer pair are similar. Therefore, linearity should not be assumed for these types of measurements until confirmed experimentally. Copyright © 2013 John Wiley & Sons, Ltd.

  12. A Fluorinated Ligand Enables Room-Temperature and Regioselective Pd-Catalyzed Fluorination of Aryl Triflates and Bromides.

    Science.gov (United States)

    Sather, Aaron C; Lee, Hong Geun; De La Rosa, Valentina Y; Yang, Yang; Müller, Peter; Buchwald, Stephen L

    2015-10-21

    A new biaryl monophosphine ligand (AlPhos, L1) allows for the room-temperature Pd-catalyzed fluorination of a variety of activated (hetero)aryl triflates. Furthermore, aryl triflates and bromides that are prone to give mixtures of regioisomeric aryl fluorides with Pd-catalysis can now be converted to the desired aryl fluorides with high regioselectivity. Analysis of the solid-state structures of several Pd(II) complexes, as well as density functional theory (DFT) calculations, shed light on the origin of the enhanced reactivity observed with L1.

  13. Thermal Rearrangement of Allyl Substituted Unsymmetric 4H-1,2,4-Triazoles to the Corresponding 1H-1,2,4-triazoles

    Directory of Open Access Journals (Sweden)

    Per H.J. Carlsen

    2001-04-01

    Full Text Available A series of neat 4-(2-alkenyl substituted 5-methyl-3-phenyl-4H-1,2,4-triazoles were thermolyzed at 320 oC producing a rearrangement products, of which the regioisomeric 1- and 2-substituted triazoles were the main products. The group migrations were rationalized in terms of consecutive SN2-type reactions. This mechanism was supported by a study of the alkylations of the triazoles which gave similar product mixtures. 4-(2-alkenyl substituted 3-phenyl-4H-1,2,4-triazoles, on the other hand, gave predominantly elimination products.

  14. Symmetrically and Unsymmetrically Bridged Methylenebis(allopurinols: Synthesis of Dimeric Potential Anti-Gout Drugs

    Directory of Open Access Journals (Sweden)

    Frank Seela

    2007-03-01

    Full Text Available Liquid-liquid phase transfer alkylation of 4-methoxy-pyrazolo[3,4-d]-pyrimidine (1a with a dichloromethane/dibromomethane mixture (3:1, v/v gave the regioisomeric methylenebis(heterocycles 3a–5a. These were converted by dilute aqueous sodium hydroxide containing dimethylsulfoxide (DMSO at concentrations between 0 and 60 vol-% into the methylenebis(allopurinols 3b–5b by nucleophilic SNAr reactions at C(4. The effect of DMSO on the reaction kinetics was investigated.

  15. Synthesis, DNA binding and cytotoxic evaluation of aminoquinoline scaffolds

    Indian Academy of Sciences (India)

    Gopal Senthil Kumar; Mohamed Ashraf Ali; Tan Soo Choon; Rajendra Prasad Karnam Jayarampillai

    2016-03-01

    An effortless synthetic route has been developed for the synthesis of a new class of aminoquinoline substituted isoindolin-1,3-diones from regio-isomerical hydrazinylquinolines with phthalic anhydride in presence of Eaton’s reagent. DNA binding studies of selected isomeric compounds showed interaction withDNA via intercalation mode with higher binding affinity of 4-substituted quinolines rather than 2-substituted counterparts. Further, all compounds were screened for cytotoxic activity against three human cancer cell lines,among them compound 2c outranged standard doxorubicin against CCRF-CEM cell line.

  16. Expedient synthesis of coumarin-coupled triazoles via 'click chemistry' leading to the formation of coumarin-triazole-sugar hybrids.

    Science.gov (United States)

    Kumar, K Karthik; Kumar, R Mahesh; Subramanian, V; Das, T Mohan

    2010-11-02

    Coumarin-based triazoles were synthesized from 3-azidomethylcoumarin and a terminal acetylenic compound. Uncatalysed thermal conditions result in a mixture of both 1,4- and 1,5-regioisomers or the thermodynamically more stable 1,4-regioisomer, whereas the Cu(I)-catalysed reaction affords only the favourable 1,4-regioisomer. B3LYP/6-31G(d) level of theory has been used to calculate geometry and frequency features of the reactants, transition states (TSs) and products. Computational studies further reveal that 1,4-regioisomeric products are more favourable and also thermodynamically more stable compared to the 1,5-regioisomers.

  17. Improved regioselectivity in pyrazole formation through the use of fluorinated alcohols as solvents: synthesis and biological activity of fluorinated tebufenpyrad analogs.

    Science.gov (United States)

    Fustero, Santos; Román, Raquel; Sanz-Cervera, Juan F; Simón-Fuentes, Antonio; Cuñat, Ana C; Villanova, Salvador; Murguía, Marcelo

    2008-05-01

    The preparation of N-methylpyrazoles is usually accomplished through reaction of a suitable 1,3-diketone with methylhydrazine in ethanol as the solvent. This strategy, however, leads to the formation of regioisomeric mixtures of N-methylpyrazoles, which sometimes are difficult to separate. We have determined that the use of fluorinated alcohols such as 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as solvents dramatically increases the regioselectivity in the pyrazole formation, and we have used this modification in a straightforward synthesis of fluorinated analogs of Tebufenpyrad with acaricide activity.

  18. Modular synthesis of cell-permeating 2-ketoglutarate esters.

    Science.gov (United States)

    Zengeya, Thomas T; Kulkarni, Rhushikesh A; Meier, Jordan L

    2015-05-15

    Cell-permeating esters of 2-ketoglutarate (2-KG) have been synthesized through a convergent sequence from two modules in two and three steps, respectively. This route provides access to a full series of mono- and disubstituted 2-KG esters, enabling us to define the effect of regioisomeric masking on metabolite release and antihypoxic activity in cell-based assays. In addition to providing insight into the biological activity of cell permeable 2-KG esters, the straightforward and modular nature of this synthetic route may prove useful for the development of next-generation 2-KG analogues for diagnostic and therapeutic applications.

  19. Regioselective dimerization of ferulic acid in a micellar solution

    DEFF Research Database (Denmark)

    Larsen, E; Andreasen, Mette Findal; Christensen, L P

    2001-01-01

    that regioisomeric ferulic acid dehydrodimers can be obtained in one step from trans-ferulic acid after attachment to these micelles and using the biomimetic peroxidase-H2O2 system. The surfactant hexadecyltrimethylammonium hydroxide yielded trans-4-(4-hydroxy-3-methoxybenzylidene)-2-(4-hydroxy-3-methoxyphenyl)-5......-oxotetrahydrofuran-3-carboxylic acid (25%), (E,E)-4,4'-dihydroxy-5,5'-dimethoxy-3,3'-bicinnamic acid (21%), and trans-5-[(E)-2-carboxyvinyl]-2-(4-hydroxy-3-methoxyphenyl)-7-methoxy-2,3-dihydrobenzofuran-3-carboxylic acid (14%), whereas the surfactant tetradecyltrimethylammonium bromide gave 4-cis, 8-cis-bis(4...

  20. Synthesis and properties of ApA analogues with shortened phosphonate internucleotide linkage.

    Science.gov (United States)

    Králíková, Sárka; Buděšínský, Miloš; Barvík, Ivan; Masojídková, Milena; Točík, Zdeněk; Rosenberg, Ivan

    2011-01-01

    A complete series of the 2 '-5 ' and 3 '-5 ' regioisomeric types of r(ApA) and 2 '-d(ApA) analogues with the α-hydroxy-phosphonate C3 '-O-P-CH(OH)-C4 ″ internucleotide linkage, isopolar but non-isosteric with the phosphodiester one, were synthesized and their hybridization properties with polyU studied. Due to the chirality on the 5 '-carbon atom of the modified internucleotide linkage bearing phosphorus and hydroxy moieties, each regioisomeric type of ApA dimer is split into epimeric pairs. To examine the role of the 5 '-hydroxyl of the α-hydroxy-phosphonate moiety during hybridization, the appropriate r(ApA) analogues with 3 '(2 ')-O-P-CH(2)-C4 ″ linkage lacking the 5 '-hydroxyl were synthesized. Nuclear magnetic resonance (NMR) spectroscopy study on the conformation of the modified sugar-phosphate backbone, along with the hybridization measurements, revealed remarkable differences in the stability of complexes with polyU, depending on the 5 '-carbon atom configuration. Potential usefulness of the α-hydroxy-phosphonate linkage in modified oligoribonucleotides is discussed.

  1. Comparison Between in Vivo and in Vitro Metabolite Production of Morus nigra.

    Science.gov (United States)

    Ferrari, F; Monacelli, B; Messana, I

    1999-02-01

    Nine flavonoids and seven Diels-Alder type adducts were isolated from the acetonic extract of MORUS NIGRA I. root bark, and three flavonoids and six Diels-Alder type adducts were isolated from the acetonic extract of M. NIGRA L. callus. However, none of the metabolites isolated from the root bark was found in the cell culture. Moreover, adducts isolated from the plant and cell culture showed not only a different cyclohexene ring substitution but also a different stereochemistry, that was found CIS-TRONS in the metabolites isolated from callus, and TRANS-TRANS in those isolated from the root bark.

  2. Synthesis of a des-B-ring bryostatin analogue leads to an unexpected ring expansion of the bryolactone core.

    Science.gov (United States)

    Kraft, Matthew B; Poudel, Yam B; Kedei, Noemi; Lewin, Nancy E; Peach, Megan L; Blumberg, Peter M; Keck, Gary E

    2014-09-24

    A convergent synthesis of a des-B-ring bryostatin analogue is described. This analogue was found to undergo an unexpected ring expansion of the bryolactone core to generate the corresponding 21-membered macrocycle. The parent analogue and the ring-expanded product both displayed nanomolar binding affinity for PKC. Despite containing A-ring substitution identical to that of bryostatin 1 and displaying bryostatin-like biological function, the des-B-ring analogues displayed a phorbol-like biological function in cells. These studies shed new light on the role of the bryostatin B-ring in conferring bryo-like biological function to bryostatin analogues.

  3. 2,4,8,10,13-Pentamethyl-6-phenyl-13,14-dihydro-12H-6λ5-dibenzo[d,i][1,3,7,2]dioxazaphosphecin-6-thione

    Directory of Open Access Journals (Sweden)

    M. Krishnaiah

    2010-01-01

    Full Text Available In the title compound, C25H28NO2PS, the cyclodecene ring exhibits a crown conformation. The two dimethylbenzene rings which are fused symmetrically on either side of the ten-membered ring, make dihedral angles of 20.2 (1 and 18.0 (1°. The phenyl ring substituted at P is perpendicular to the heterocyclic ring, making a dihedral angle of 88.4 (1°. The crystal structure is stabilized by very weak intramolecular C—H...O hydrogen bonding.

  4. Poly[μ-aqua-μ5-[2-(2,3,6-trichlorophenylacetato]-caesium

    Directory of Open Access Journals (Sweden)

    Graham Smith

    2013-12-01

    Full Text Available In the structure of the title complex, [Cs(C8H4Cl3O2(H2O]n, the caesium salt of the commercial herbicide fenac [(2,3,6-trichlorophenylacetic acid], the irregular eight-coordination about Cs+ comprises a bidentate O:Cl-chelate interaction involving a carboxylate-O atom and an ortho-related ring-substituted Cl atom, which is also bridging, a triple-bridging carboxylate-O atom and a bridging water molecule. A two-dimensional polymer is generated, lying parallel to (100, within which there are water–carboxylate O—H...O hydrogen-bonding interactions.

  5. Density functional study on ionic liquid of 1-propyl-4,5-dibromo-3-methylimidazolium bromide

    Science.gov (United States)

    Lü, Renqing; Wang, Shutao; Lu, Yukun

    2011-03-01

    The density functional method and DNP basis set were employed to study 1-pair, 2-pair, and 3-pair of cation-anion interactions of 1-propyl-4,5-dibromo-3-methylimidazolium bromides. The calculated results reveal that H 2 atoms of 1-propyl-4,5-dibromo-3-methylimidazolium form hydrogen bondings with Br -. The natural bond orbital (NBO) and atoms in molecules (AIM) analyzes show that halogen bondings between Br - anion and imidazolium ring substituted bromine atoms were formed in the gas phase, in agreement with the crystal phase of 1-propyl-4,5-dibromo-3-methylimidazolium bromide which is governed by both hydrogen bondings and halogen bondings.

  6. Enantiopure 1,4,5-trisubstituted 1,2,3-triazoles from carbohydrates: applications of organoselenium chemistry.

    Science.gov (United States)

    Bhaumik, Atanu; Samanta, Supravat; Pathak, Tanmaya

    2014-08-01

    A wide range of stable vinyl selenone-modified furanosides has been synthesized for the first time. These 2π-partners undergo 1,3-dipolar cycloaddition reactions with a wide range of organic azides to afford enantiopure trisubstituted triazoles. Furanosyl rings opened up during triazole synthesis to generate polyfunctionalized molecules, ready to undergo further transformations. This strategy is one of the most convenient methods for the synthesis of enantiopure 1,4,5-trisubstituted 1,2,3-triazoles where the chiral components are attached to C-4 or C-5 position of triazole ring. These triazoles are formed in a regioselective manner, and several pairs of regioisomeric triazoles have also been synthesized. The approach affords densely functionalized triazoles, which are amenable to further modifications because of the presence of aldehyde and hydroxyl groups. This powerful and practical route adds to the arsenals of chemists and biologists interested in the synthesis and applications of triazoles.

  7. Microbial transformations 59: first kilogram scale asymmetric microbial Baeyer-Villiger oxidation with optimized productivity using a resin-based in situ SFPR strategy.

    Science.gov (United States)

    Hilker, Iris; Wohlgemuth, Roland; Alphand, Véronique; Furstoss, Roland

    2005-12-20

    This study is demonstrating the scale up of asymmetric microbial Baeyer-Villiger oxidation of racemic bicyclo[3.2.0]hept-2-en-6-one (1) to the kilogram scale using a 50 L bioreactor. The process has been optimized with respect to bottlenecks identified in downscaled experiments. A high productivity was obtained combining a resin-based in situ substrate feeding and product removal methodology (in situ SFPR), a glycerol feed control, and an improved oxygenation device (using a sintered-metal sparger). As expected both regioisomeric lactones [(-)-(1S,5R)-2 and (-)-(1R,5S)-3] were obtained in nearly enantiopure form (ee > 98%) and good yield. This represents the first example of such an asymmetric Baeyer-Villiger biooxidation reaction ever operated at that scale. This novel resin-based in situ SFPR technology therefore clearly opens the way to further (industrial) upscaling of this highly valuable (asymmetric) reaction.

  8. Formation of isoprostane bicyclic endoperoxides from the autoxidation of cholesteryl arachidonate.

    Science.gov (United States)

    Yin, Huiyong; Havrilla, Christine M; Morrow, Jason D; Porter, Ned A

    2002-07-03

    Autoxidation of polyunsaturated fatty acids and esters leads to a complex mixture containing hydroperoxides and cyclic peroxides. Prostaglandin bicyclic endoperoxides have been detected from the autoxidation of cholesteryl arachidonate by LC-MS and GC-MS techniques. All four possible types (I-IV) of bicyclic endoperoxides have been found starting from different regioisomeric hydroperoxides of cholesteryl arachidonate. Furthermore, the stereochemistry of Type IV bicyclic endoperoxides has been determined by conversion to pentafluorobenzyl (PFB) ester, trimethylsilyl (TMS) derivatives, and comparison with synthetic standards by the use of GC-MS. All eight possible diastereomers of the derivatized isoprostanes were observed and were separated by gas chromatography. The bicyclic endoperoxides with the two alkyl chains syn on the cyclopentane ring were formed preferentially to those with anti configuration, a result anticipated from earlier work. Substantial amounts of the anti-substituted isoprostanes, including PGF(2)(alpha), were, however, observed in the product mixture.

  9. Synthesis, single crystal and antitumor activities of benzimidazole-quinazoline hybrids.

    Science.gov (United States)

    Sharma, Alka; Luxami, Vijay; Paul, Kamaldeep

    2013-06-01

    A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by (1)H and (13)C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.

  10. Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole.

    Science.gov (United States)

    Paul, Kamaldeep; Sharma, Alka; Luxami, Vijay

    2014-01-15

    By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric molecules with substituted primary amines have been synthesized. Evaluation of these molecules over 60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound 10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of compounds with GI50 value of 1.64 μM. Compound 11 (GI50 value of 0.81 μM) showed almost twenty and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while compound 12 (GI50 value of 4.52 μM) has four fold more activity than quinazoline and benzimidazole analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon cancer cell lines and prostate cancer cell lines at five dose concentrations with GI50 values of 0.34 and 0.31 μM, respectively.

  11. Regioisomers of octanoic acid-containing structured triacylglycerols analyzed by tandem mass spectrometry using ammonia negative ion chemical ionization

    DEFF Research Database (Denmark)

    Kurvinen, J.P.; Mu, Huiling; Kallio, H.

    2001-01-01

    Tandem mass spectrometry based on ammonia negative ion chemical ionization and sample introduction via direct exposure probe was applied to analysis of regioisomeric structures of octanoic acid containing structured triacylglycerols (TAG) of type MML, MLM, MLL, and LML (M, medium-chain fatty acid......; L, long-chain fatty acid). Collision-induced dissociation of deprotonated parent TAG with argon was used to produce daughter ion spectra with appropriate fragmentation patterns for structure determination. Fatty acids constituting the TAG molecule were identified according to [RCO2](-) ions...... in the daughter ion spectra. With the standard curve for ratios of [M - H - RCO2H - 100](-) ions corresponding to each [RCO2](-) ion, determined with known mixtures of sn-1/3 and sn-2 regioisomers of structured TAG, it was possible to determine the proportions of different regioisomers in unknown samples...

  12. A Novel and Highly Regioselective Synthesis of New Carbamoylcarboxylic Acids from Dianhydrides

    Science.gov (United States)

    Ochoa-Terán, Adrián; Estrada-Manjarrez, Jesús; Martínez-Quiroz, Marisela; Landey-Álvarez, Marco A.; Alcántar Zavala, Eleazar; Pina-Luis, Georgina; Santacruz Ortega, Hisila; Gómez-Pineda, Luis Enrique; Ramírez, José-Zeferino; Chávez, Daniel; Montes Ávila, Julio; Labastida-Galván, Victoria; Ordoñez, Mario

    2014-01-01

    A regioselective synthesis has been developed for the preparation of a series of N,N′-disubstituted 4,4′-carbonylbis(carbamoylbenzoic) acids and N,N′-disubstituted bis(carbamoyl) terephthalic acids by treatment of 3,3′,4,4′-benzophenonetetracarboxylic dianhydride (1) and 1,2,4,5-benzenetetracarboxylic dianhydride (2) with arylalkyl primary amines (A-N). The carbamoylcarboxylic acid derivatives were synthesized with good yield and high purity. The specific reaction conditions were established to obtain carbamoyl and carboxylic acid functionalities over the thermodynamically most favored imide group. Products derived from both anhydrides 1 and 2 were isolated as pure regioisomeric compounds under innovative experimental conditions. The chemo- and regioselectivity of products derived from dianhydrides were determined by NMR spectroscopy and confirmed by density functional theory (DFT). All products were characterized by NMR, FTIR, and MS. PMID:24511299

  13. A Novel and Highly Regioselective Synthesis of New Carbamoylcarboxylic Acids from Dianhydrides

    Directory of Open Access Journals (Sweden)

    Adrián Ochoa-Terán

    2014-01-01

    Full Text Available A regioselective synthesis has been developed for the preparation of a series of N,N′-disubstituted 4,4′-carbonylbis(carbamoylbenzoic acids and N,N′-disubstituted bis(carbamoyl terephthalic acids by treatment of 3,3′,4,4′-benzophenonetetracarboxylic dianhydride (1 and 1,2,4,5-benzenetetracarboxylic dianhydride (2 with arylalkyl primary amines (A-N. The carbamoylcarboxylic acid derivatives were synthesized with good yield and high purity. The specific reaction conditions were established to obtain carbamoyl and carboxylic acid functionalities over the thermodynamically most favored imide group. Products derived from both anhydrides 1 and 2 were isolated as pure regioisomeric compounds under innovative experimental conditions. The chemo- and regioselectivity of products derived from dianhydrides were determined by NMR spectroscopy and confirmed by density functional theory (DFT. All products were characterized by NMR, FTIR, and MS.

  14. Ring positional differentiation of isomeric N-alkylated fluorocathinones by gas chromatography/tandem mass spectrometry.

    Science.gov (United States)

    Westphal, Folker; Junge, Thomas

    2012-11-30

    In analogy to our previously published procedure for the differentiation of regioisomeric fluoroamphetamines a method was developed, to differentiate ring positional isomeric fluorocathinones by product ion spectrometry of ions generated by chemical ionization (CI) under GC-MS conditions using methane as reagent gas. N-alkylated ortho-, meta- and para-fluorocathinones could be unequivocally differentiated by product ion spectrometry of the hydrogen fluoride loss ions [M+H-HF](+) using a triple quadrupole mass spectrometer with argon as collision gas under normalized collision conditions. This method enables the differentiation of ring positional isomers of fluorocathinones even in complex mixtures and low concentrations. The applicability of the method was shown by the analysis of synthesized N-alkylated ortho-, meta- and para-fluorocathinones and seized designer drug mixtures.

  15. Synthesis and biological evaluation of a new series of 2-amino-3-aroyl thiophene derivatives as agonist allosteric modulators of the A1 adenosine receptor. A position-dependent effect study.

    Science.gov (United States)

    Romagnoli, Romeo; Baraldi, Pier Giovanni; Lopez-Cara, Carlota; Cruz-Lopez, Olga; Moorman, Allan R; Massink, Arnault; IJzerman, Adriaan P; Vincenzi, Fabrizio; Borea, Pier Andrea; Varani, Katia

    2015-08-28

    The 2-amino-3-(p-chlorobenzoyl)thiophene scaffold has been widely employed as a pharmacophore for the identification of small molecules acting as allosteric modulators at the adenosine A1 receptor. A new series of 2-amino-3-(p-chlorobenzoyl)-4-benzyl-5-arylthiophene derivatives, characterized by the absence as well as the presence of electron-releasing or electron-withdrawing groups on the phenyl ring at the 4- and 5-positions of the thiophene ring, were identified as positive allosteric enhancers at the adenosine A1 receptor in binding (saturation, competition and dissociation kinetics) and functional assays. To better understand the positional requirements of substituents on the 2-amino-3-(p-chlorobenzoyl)thiophene core, the corresponding regioisomeric 4-aryl-5-benzylthiophene analogues were synthesized and found to possess reduced allosteric enhancer activity. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  16. Recent advances in the ruthenium-catalyzed hydroarylation of alkynes with aromatics: synthesis of trisubstituted alkenes.

    Science.gov (United States)

    Manikandan, Rajendran; Jeganmohan, Masilamani

    2015-11-14

    The hydroarylation of alkynes with substituted aromatics in the presence of a metal catalyst via chelation-assisted C-H bond activation is a powerful method to synthesize trisubstituted alkenes. Chelation-assisted C-H bond activation can be done by two ways: (a) an oxidative addition pathway and (b) a deprotonation pathway. Generally, a mixture of cis and trans stereoisomeric as well as regioisomeric trisubstituted alkenes was observed in an oxidative addition pathway. In the deprotonation pathway, the hydroarylation reaction can be done in a highly regio- and stereoselective manner, and enables preparation of the expected trisubstituted alkenes in a highly selective manner. Generally, ruthenium, rhodium and cobalt complexes are used as catalysts in the reaction. In this review, a ruthenium-catalyzed hydroarylation of alkynes with substituted aromatics is covered completely. The hydroarylation reaction of alkynes with amide, azole, carbamate, phosphine oxide, amine, acetyl, sulfoxide and sulphur directed aromatics is discussed.

  17. Appearance and distribution of regioisomers in metallo- and serine-protease-catalysed acylation of sucrose in N,N-dimethylformamide

    DEFF Research Database (Denmark)

    Lie, Aleksander; Meyer, Anne S.; Pedersen, Lars Haastrup

    2014-01-01

    M in the reaction without protein, both after 48 h. The detected appearance of the sucrose laurate regioisomers largely corresponded to the apparent rates of formation, and 2-O-lauroyl sucrose was among the first regioisomers to appear in all reactions. The observed sucrose laurate regioisomeric distribution after...... laurate was obtained in yields from 12 to 53% after 48 h under different catalytic conditions. The serine protease ALP-901, derived from a Streptomyces sp., produced the highest yield at this reaction time, while reaction with the zinc-protease thermolysin achieved the overall highest yield (63%) after 6...... h, with only monoesters synthesised. The total conversion of sucrose after 48 h ranged from 19 to 96%. The highest degree of conversion was observed in the reaction with thermolysin, while the reactions without protein and with ALP-901 resulted in 82% and 66% sucrose conversion, respectively. 2-O...

  18. Assembly of synthetic Aβ miniamyloids on polyol templates

    Directory of Open Access Journals (Sweden)

    Sebastian Nils Fischer

    2015-12-01

    Full Text Available Covalent dynamic chemistry is used to mimic the first steps of the highly cooperative fibril formation of Aβ peptides. For that purpose, Aβ peptide pentapeptide boronic acids 1 and 2 were synthesized by solid-phase peptide synthesis and studied in esterification experiments with polyhydroxylated templates. The bis-hydroxylated dipeptide Hot=Tap serves as a template of adjustable degree of oligomerization which spontaneously forms boronic esters with peptides of type 1 and 2. Nuclear magnetic resonance can differentiate between regioisomeric boronic esters and identifies preferred sites of esterification on the dimeric template 9. 2-Formylphenylboronic acid (14 is used to link the parent pentapeptide Leu-Val-Phe-Phe-Ala to the template 16 to obtain threefold boronic ester 17. The miniamyloid 17 assembles from seven components by imine and boronic ester bonds between the peptides and the template. The relative orientation and spacing of the peptides mimic the assembly of peptides in Alzheimer β-amyloids.

  19. From thiourea to bicyclic structures: an original route to imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines.

    Science.gov (United States)

    Landreau, Cyrille; Deniaud, David; Meslin, Jean Claude

    2003-06-13

    We report an example of an efficient regioselective synthesis of biheterocyclic compounds using thiourea as starting material. In fact, N,N'-bis(dimethylaminomethylene)thiourea (1), easily prepared by double condensation of N,N-dimethylformamide dimethyl acetal with thiourea, can be reacted with haloketones or acrylic dienophiles to give thiazolic (2) and thiazinic (3) diazadienes, respectively, themselves undergoing cyclization reactions to yield imidazo[2,1-b]thiazoles, 5H-thiazolo[3,2-a]pyrimidines, 7H-imidazo[2,1-b][1,3]thiazines, and 2H,6H-pyrimido[2,1-b][1,3]thiazines without any regioisomeric ambiguity. This straightforward route represents an original and unambiguously regioselective pathway to these valuable heterocycles.

  20. Access to Silylated Pyrazole Derivatives by Palladium-Catalyzed C-H Activation of a TMS group.

    Science.gov (United States)

    Mistico, Laetitia; Querolle, Olivier; Meerpoel, Lieven; Angibaud, Patrick; Durandetti, Muriel; Maddaluno, Jacques

    2016-07-04

    A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single-step cyclization relying on the Pd-catalyzed activation of a non-activated C(sp(3) )-H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation-deprotonation (CMD) mechanism.

  1. Analogues of doxanthrine reveal differences between the dopamine D 1 receptor binding properties of chromanoisoquinolines and hexahydrobenzo[a]phenanthridines

    Science.gov (United States)

    Cueva, J.P.; Chemel, B.R.; Juncosa, J.I.; Lill, M.A.; Watts, V.J.; Nichols, D.E.

    2012-01-01

    Efforts to develop selective agonists for dopamine D 1-like receptors led to the discovery of dihydrexidine and doxanthrine, two bioisosteric ??-phenyldopamine-type full agonist ligands that display selectivity and potency at D 1-like receptors. We report herein an improved methodology for the synthesis of substituted chromanoisoquinolines (doxanthrine derivatives) and the evaluation of several new compounds for their ability to bind to D 1- and D 2-like receptors. Identical pendant phenyl ring substitutions on the dihydrexidine and doxanthrine templates surprisingly led to different effects on D 1-like receptor binding, suggesting important differences between the interactions of these ligands with the D 1 receptor. We propose, based on the biological results and molecular modeling studies, that slight conformational differences between the tetralin and chroman-based compounds lead to a shift in the location of the pendant ring substituents within the receptor. ?? 2011 Elsevier Ltd. All rights reserved.

  2. [GC-FTIR analysis of structural isomers from hydrogenation products of p-phenylphenol].

    Science.gov (United States)

    Xin, Jun-Na; Xu, Qiang; Zhang, Hua; Yang, Xi-Chuan; Lü, Lian-Hai

    2008-04-01

    The hydrogenation of p-phenylphenol is a consecutive and parallel complex reaction. Owing to the difference in the hydrogenation ability of the two benzene rings in pphenylphenol, the hydrogenation products contained several structural isomers, which can not be identified by normal analytical method. However, the reaction mixture was effectively separated and identified by GC-FTIR technique. According to the characteristic wave numbers of benzene ring substituted at different positions, the main product was confirmed to be p-cyclohexylphenol, and the two typical by-products were p-phenylcyclohexanol and p-cyclohexylcyclohexanol, respectively. Each product has several stereo-isomers. GC-MS, melting point measurement and NMR proved the accuracy of GC-FTIR results, indicating that GC-IR is an useful and rapid method for analyzing structural isomers of organic compounds.

  3. 'Smoking' mephedrone: the identification of the pyrolysis products of 4-methylmethcathinone hydrochloride.

    Science.gov (United States)

    Kavanagh, Pierce; O'Brien, John; Power, John D; Talbot, Brian; McDermott, Seán D

    2013-05-01

    The ring-substituted cathinone - mephedrone - has gained popularity among recreational drug users over the past several years. It is generally consumed orally or by snorting but reports indicate that it is also ingested by vaporization/inhalation. This study examines the pyrolysis products produced by heating mephedrone under using simulated 'meth pipe' conditions. Thirteen pyrolysis products were identified, the major ones being iso-mephedrone, 4-methylpropiophenone, 4-methylphenylacetone, two pyrazine derivatives formed by dimerization of mephedrone, N-methylated mephedrone (N,N,4-trimethylcatinone), two hydroxylated oxidation products and a diketone. Other minor products formed were identified as 4-methylacetophenone, two α-chloro ketones and N-methylated iso-mephedrone.

  4. The biosynthesis of allelopathic di-C-glycosylflavones from the roots of Desmodium incanum (G. Mey.) DC.

    Science.gov (United States)

    Hao, Bing; Caulfield, John C; Hamilton, Mary L; Pickett, John A; Midega, Charles A O; Khan, Zeyaur R; Wang, Junru R; Hooper, Antony M

    2015-12-28

    The allelopathic root exudate of the drought-tolerant subsistence cereal intercrop D. incanum, protecting against the parasitic weed Striga hermonthica, comprises a number of di-C-glycosylflavones specifically containing C-glucosyl, C-galactosyl and C-arabinosyl moieties. Here we demonstrate that the biosynthesis of all compounds containing a C-glucose involves C-glucosylation of 2-hydroxynaringenin with subsequent C-galactosylation, C-glucosylation or C-arabinosylation. In addition, the crude soluble enzyme extract converts two fluorinated 2-hydroxyflavanone analogues to corresponding mono- and di-C-glycosylflavones demonstrating that some differences in C-ring substitution can be tolerated by the plant enzymes. Elucidating the biosynthesis of these C-glycosylflavones (CGFs) has the potential to open up opportunities for transferring the enzymic and genetic basis for the S. hermonthica inhibiting allelopathic trait to food crop plants.

  5. Synthesis, Docking Studies and Biological Evaluation of Benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl-propan-1-one Derivatives on 5-HT1A Serotonin Receptors

    Directory of Open Access Journals (Sweden)

    Ramiro Araya-Maturana

    2012-02-01

    Full Text Available A series of novel benzo[b]thiophen-2-yl-3-(4-arylpiperazin-1-yl-propan-1-one derivatives 6a–f, 7a–f and their corresponding alcohols 8a–f were synthesized and evaluated for their affinity towards 5-HT1A receptors. The influence of arylpiperazine moiety and benzo[b]thiophene ring substitutions on binding affinity was studied. The most promising analogue, 1-(benzo[b]thiophen-2-yl-3-(4-(pyridin-2-ylpiperazin-1-ylpropan-1-one (7e displayed micromolar affinity (Ki = 2.30 μM toward 5-HT1A sites. Docking studies shed light on the relevant electrostatic interactions which could explain the observed affinity for this compound.

  6. Synthesis and characterization of phenylethynylcarbonyl terminated novel thermosetting imide compound

    Directory of Open Access Journals (Sweden)

    H. Kimura

    2013-02-01

    Full Text Available Phenylethynyl terminated novel imide compound based on 1,3-bis(3-aminophenoxybenzene (APB and phenylethynyl trimellitic anhydride (PETA were prepared. The curing behavior of phenylethynyl terminated imide compound was investigated by differential scanning calorimetry and Fourier transform infrared spectrometry. The curing reaction of phenylethynylcarbonyl end group completed at 220°C, and proceeded much faster than that of phenylethynyl end group. Glass transition temperature of the thermosetting resin from phenylethynylcarbonyl terminated novel imide compound determined by dynamic mechanical analysis was almost the same as that of o-cresolnovolac type epoxy resin. In addition, the thermosetting resin from phenylethynylcarbonyl terminated novel imide compound exhibited excellent thermal and dimensional stabilities. These excellent properties of these phenylethynyl terminated imide compound might be due to the incorporation of alkene group or aromatic ring substitutes in the backbones, which might enhance the chain interaction (molecular packing and reduce the molecular chain mobility.

  7. Thermolysis of High-Density Polyethylene to Petroleum Products

    Directory of Open Access Journals (Sweden)

    Sachin Kumar

    2013-01-01

    Full Text Available Thermal degradation of plastic polymers is becoming an increasingly important method for the conversion of plastic materials into valuable chemicals and oil products. In this work, virgin high-density polyethylene (HDPE was chosen as a material for pyrolysis. A simple pyrolysis reactor system has been used to pyrolyse virgin HDPE with an objective to optimize the liquid product yield at a temperature range of 400°C to 550°C. The chemical analysis of the HDPE pyrolytic oil showed the presence of functional groups such as alkanes, alkenes, alcohols, ethers, carboxylic acids, esters, and phenyl ring substitution bands. The composition of the pyrolytic oil was analyzed using GC-MS, and it was found that the main constituents were n-Octadecane, n-Heptadecane, 1-Pentadecene, Octadecane, Pentadecane, and 1-Nonadecene. The physical properties of the obtained pyrolytic oil were close to those of mixture of petroleum products.

  8. Phemindole, a synthetic di-indole derivative maneuvers the store operated calcium entry (SOCE to induce potent anti-carcinogenic activity in human triple negative breast cancer cells

    Directory of Open Access Journals (Sweden)

    Supriya eChakraborty

    2016-05-01

    Full Text Available Triple-negative breast cancer (TNBC, is a specific subtype of epithelial breast tumours that are immuno-histochemically negative for the protein expression of the estrogen receptor (ER, the progesterone receptor (PR and lack over expression/gene amplification of HER2. This subtype of breast cancers is highly metastatic, shows poor prognosis and hence represents an important clinical challenge to researchers worldwide. Thus alternative approaches of drug development for TNBC have gained utmost importance in the present times. Dietary indole and its derivatives have gained prominence as anti-cancer agents and new therapeutic approaches are being developed to target them against TNBC. But a major drawback with 3, 3’di Indolyl methane (DIM is their poor bioavailability and high effective concentration against TNBC. However the Aryl methyl ring substituted analogs of DIM display interesting anti-cancer activity in breast cancer cells. In the current study we report the synthesis of a novel synthetic aryl methyl ring substituted analog of DIM, named as Phemindole as an effective anti-tumor agent against TNBC cells. Furthermore, we enumerated that Phemindole caused ROS mediated mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, Phemindole mediated Store Operated Calcium Entry (SOCE retardation favored inactivation of STIM1 and henceforth activated ER stress to induce apoptosis in TNBC cells. Simultaneously, Phemindole was also found to restrict the in-vitro cell migration through its anti mitotic property and pFAK regulation. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of Phemindole. Thus our results cumulatively propose Phemindole as a new chemotherapeutic regime which might be effective to target the deadly aspects of the TNBC.

  9. DFT evidence for a stepwise mechanism in the O-neophyl rearrangement of 1,1-diarylalkoxyl radicals.

    Science.gov (United States)

    Bietti, Massimo; Ercolani, Gianfranco; Salamone, Michela

    2007-06-08

    Hybrid DFT calculations of the potential energy surface (PES) relative to the O-neophyl rearrangement of a series of ring-substituted 1,1-diarylalkoxyl radicals have been carried out at the UB3LYP/6-31G(d) level of theory. On the basis of the computational data, the rearrangement can be described as a consecutive reaction of the type a b --> c (see above graphic), and the steady-state approximation could be applied in all cases to the intermediate b. The first-order rearrangement rate constants [kobs = k1k2/(k-1 + k2)] were thus obtained from the computed activation free-energies and were compared with the experimental rate constants measured previously in MeCN solution by laser flash photolysis. An excellent agreement is observed along the two series, which strongly supports the hypothesis that the O-neophyl rearrangement of 1,1-diarylalkoxyl radicals proceeds through the formation of the reactive 1-oxaspiro [2,5]octadienyl radical intermediate. This is in contrast to previous hypotheses that involve either a long-lived intermediate or the absence of this intermediate along the reaction path. The calculated rearrangement free-energies decrease upon going from the methoxy-substituted radical (Delta G degrees = -16.4 kcal x mol-1) to the nitro-substituted one (Delta G degrees = -21.8 kcal x mol-1), which follows a trend that is similar to the one observed for the CAr-O bond dissociation enthalpies (BDEs) of ring-substituted anisoles. This evidence indicates that in the O-neophyl rearrangement the effect of ring substituents on the strength of the newly formed CAr-O bond plays an important role.

  10. A method for determining regioisomer abundances of polyunsaturated triacylglycerols in omega-3 enriched fish oils using reversed-phase liquid chromatography and triple-stage mass spectrometry.

    Science.gov (United States)

    Cubero Herrera, Lisandra; Ramaley, Louis; Potvin, Michael A; Melanson, Jeremy E

    2013-08-15

    Reversed-phase high performance liquid chromatography (RP-HPLC), followed by post-column addition of lithium salts and electrospray ionisation triple-stage mass spectrometry (ESI-MS(3)) of lithiated TAG adducts, is shown to provide a useful method for the positional analysis of triacylglycerols (TAGs) in fish oils containing eicosapentaenoic (EPA, 20:5) and docosahexaenoic acids (DHA, 22:6). One prominent fragmentation pathway in the ESI-MS(3) of these adduct ions involves the loss of a fatty acid from the sn-1/3 position in the first step followed by the loss of an α,β-unsaturated fatty acid from the sn-2 position in the second. Regioisomeric TAGs of the type ABA and AAB produced abundant product ions - [ABA+Li-RACOOH-R'BCHCHCOOH](+) and [AAB+Li-RACOOH-R'ACHCHCOOH](+) - the relative intensities of which were dependent on the position of acyl substituents. Standard solutions of TAGs containing different ratios of the regioisomeric pairs MME/MEM, PPE/PEP, PPD/PDP, EEP/EPE and DDP/DPD (M=14:0, P=16:0, E=20:5, D=22:6) were analysed by ESI-MS(3) with a quadrupole linear ion trap instrument. Methodology developed on the standards was applied to quantifying the relative isomeric abundances of EPA and DHA in several fish oil samples. DHA was preferentially located at the sn-2 position in both DHA-containing TAGs studied, while EPA was either observed at near equal levels in all positions, or predominantly at the sn-1 and -3 positions in some cases. The analysis protocol allows for quantification of the designated regioisomers in one simple, rapid chromatographic procedure using a single column and has the advantage of specificity over other methods for the positional analysis of TAGs, since it eliminates interferences associated with co-eluting TAGs of the same molecular weight that yield isobaric diacylglycerol-like product ions. Crown Copyright © 2013. Published by Elsevier Ltd. All rights reserved.

  11. Structural Analysis of Unsaturated Glycosphingolipids Using Shotgun Ozone-Induced Dissociation Mass Spectrometry

    Science.gov (United States)

    Barrientos, Rodell C.; Vu, Ngoc; Zhang, Qibin

    2017-08-01

    Glycosphingolipids are essential biomolecules widely distributed across biological kingdoms yet remain relatively underexplored owing to both compositional and structural complexity. While the glycan head group has been the subject of most studies, there is paucity of reports on the lipid moiety, particularly the location of unsaturation. In this paper, ozone-induced dissociation mass spectrometry (OzID-MS) implemented in a traveling wave-based quadrupole time-of-flight (Q-ToF) mass spectrometer was applied to study unsaturated glycosphingolipids using shotgun approach. Resulting high resolution mass spectra facilitated the unambiguous identification of diagnostic OzID product ions. Using [M+Na]+ adducts of authentic standards, we observed that the long chain base and fatty acyl unsaturation had distinct reactivity with ozone. The reactivity of unsaturation in the fatty acyl chain was about 8-fold higher than that in the long chain base, which enables their straightforward differentiation. Influence of the head group, fatty acyl hydroxylation, and length of fatty acyl chain on the oxidative cleavage of double bonds was also observed. Application of this technique to bovine brain galactocerebrosides revealed co-isolated isobaric and regioisomeric species, which otherwise would be incompletely identified using contemporary collision-induced dissociation (CID) alone. These results highlight the potential of OzID-MS in glycosphingolipids research, which not only provides complementary structural information to existing CID technique but also facilitates de novo structural determination of these complex biomolecules. [Figure not available: see fulltext.

  12. Baking Reduces Prostaglandin, Resolvin, and Hydroxy-Fatty Acid Content of Farm-Raised Atlantic Salmon (Salmo salar)

    Science.gov (United States)

    Raatz, Susan K.; Golovko, Mikhail Y.; Brose, Stephen A.; Rosenberger, Thad A.; Burr, Gary S.; Wolters, William R.; Picklo, Matthew J.

    2011-01-01

    Consumption of seafood enriched in n-3 polyunsaturated fatty acids (PUFA) is associated with a decreased risk of cardiovascular disease. Several n-3 oxidation products from eicosapentaenoic acid (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) have known protective effects in the vasculature. It is not known whether consumption of cooked seafood enriched in n-3 PUFA causes appreciable consumption of lipid oxidation products. We tested the hypothesis that baking Atlantic salmon (Salmo salar) increases the level of n-3 and n-6 PUFA oxidation products over raw salmon. We measured the content of several monohydroxy-fatty acids (MHFA), prostanoids, and resolvins. Our data demonstrate that baking did not change the overall total levels of MHFA. However, baking resulted in selective regio-isomeric loss of hydroxy fatty acids from arachidonic acid (20:4n-6), and EPA while significantly increasing hydroxyl-linoleic acid levels. The content of prostanoids and resolvins were reduced several-fold with baking. The inclusion of coating upon the salmon prior to baking reduced the loss of some MHFA but had no effect upon prostanoid losses incurred by baking. Baking did not decrease n-3 PUFA content indicating that baking of salmon is an acceptable means of preparation that does not alter the potential health benefits of high n-3 seafood consumption. The extent to which the levels of MHFA, prostanoids and resolvins in the raw or baked fish have physiologic consequence for humans needs to be determined. PMID:21919483

  13. Characterization and quantification of hydroxycinnamate derivatives in Stevia rebaudiana leaves by LC-MSn.

    Science.gov (United States)

    Karaköse, Hande; Jaiswal, Rakesh; Kuhnert, Nikolai

    2011-09-28

    Stevia rebaudiana leaves are used as a zero-calorie natural sweetener in a variety of food products in Asian countries, especially in Japan. In this study, the hydroxycinnamate derivatives of S. rebaudiana have been investigated qualitatively and quantitatively by LC-MSn. Twenty-four hydroxycinnamic acid derivatives of quinic and shikimic acid were detected, and 19 of them were successfully characterized to regioisomeric levels; 23 are reported for the first time from this source. These comprise three monocaffeoylquinic acids (Mr 354), seven dicaffeoylquinic acids (Mr 516), one p-coumaroylquinic acid (Mr 338), one feruloylquinic acid (Mr 368), two caffeoyl-feruloylquinic acids (Mr 530), three caffeoylshikimic acids (Mr 336), and two tricaffeoylquinic acids (Mr 678). Cis isomers of di- and tricaffeoylquinic acids were observed as well. Three tricaffeoylquinic acids identified in stevia leaves are reported for the first time in nature. These phenolic compounds identified in stevia might affect the organoleptic properties and add additional beneficial health effects to stevia-based products.

  14. Azulenium chemistry: towards new derivatives of photochromic dihydroazulenes.

    Science.gov (United States)

    Petersen, Anne Ugleholdt; Jevric, Martyn; Elm, Jonas; Olsen, Stine T; Tortzen, Christian G; Kadziola, Anders; Mikkelsen, Kurt V; Nielsen, Mogens Brøndsted

    2016-02-28

    Here we present the preparation of a selection of azulenium ions by hydride abstraction from photochromic 1,8a-dihydroazulenes (1,8a-DHAs) incorporating two cyano groups at C-1. The reactivity of the electrophilic tropylium ring of these molecules towards lithium triisopropylsilylacetylide was investigated. The position of attack by the nucleophile depended on the substitution pattern of the azulenium cation but was in general found to occur preferentially at positions C-4, C-5, and C-6, and to a minor extent at positions C-7 and C-8. The outcome was a mixture of non-photochromic, regioisomeric DHAs. One of these compounds containing the ethynyl substituent at position C-4 was partly tautomerized to the photochromic 1,8a-dihydroazulene, which was isolated and its switching properties were investigated by UV-Vis absorption spectroscopy. Upon irradiation, it undergoes a ring-opening reaction to form a vinylheptafulvene (VHF), which in turn returns to the original DHA. The half-life of this reaction was significantly smaller than for a derivative with the alkynyl substituent placed at C-7. This fast switching behavior was according to the calculations explained by an enhancement in the stability of the reactive s-cis conformer of the VHF relative to the, still more stable, s-trans conformer, and by a smaller activation energy for this s-cis conformer to undergo ring-closure.

  15. Cytotoxic activity evaluation and QSAR study of chromene-based chalcones.

    Science.gov (United States)

    Firoozpour, Loghman; Edraki, Najmeh; Nakhjiri, Maryam; Emami, Saeed; Safavi, Maliheh; Ardestani, Sussan Kabudanian; Khoshneviszadeh, Mehdi; Shafiee, Abbas; Foroumadi, Alireza

    2012-12-01

    Chalcone and chromene motifs are synthetic or naturally occurring scaffolds with significant cytotoxic profile. Two types of novel regioisomeric chromene-chalcone hybrids, namely 1-(6-chloro or 6-methoxy-2H-chromen-3-yl)-3-phenylprop-2-en-1-one (Type A) and 3-(6-chloro or 6-methoxy-2H-chromen-3-yl)-1-phenylprop-2-en-1-one (Type B), both with different substituents on the phenyl ring attached to propenone linkage, have been evaluated for their cytotoxic activity against breast cancer cell lines (MCF-7 and MDA-MB-231). The results indicate that type A of chromene-chalcones demonstrated better cytotoxic profile than type B especially in MDA-MB-231 cell line. In addition, the growth inhibitory activity of most of the target compounds is higher than Etoposide as a reference drug. QSAR analysis of these novel compounds demonstrated that topological and geometrical parameters are among the important descriptors that influence the cytotoxic activity profile of compounds.

  16. High-Resolution α-Glucosidase Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of Antidiabetic Compounds in Eremanthus crotonoides (Asteraceae).

    Science.gov (United States)

    Silva, Eder Lana E; Lobo, Jonathas Felipe Revoredo; Vinther, Joachim Møllesøe; Borges, Ricardo Moreira; Staerk, Dan

    2016-06-16

    α-Glucosidase inhibitors decrease the cleavage- and absorption rate of monosaccharides from complex dietary carbohydrates, and represent therefore an important class of drugs for management of type 2 diabetes. In this study, a defatted ethyl acetate extract of Eremanthus crotonoides leaves with an inhibitory concentration (IC50) of 34.5 μg/mL towards α-glucosidase was investigated by high-resolution α-glucosidase inhibition profiling combined with HPLC-HRMS-SPE-NMR. This led to identification of six α-glucosidase inhibitors, namely quercetin (16), trans-tiliroside (17), luteolin (19), quercetin-3-methyl ether (20), 3,5-di-O-caffeoylquinic acid n-butyl ester (26) and 4,5-di-O-caffeoylquinic acid n-butyl ester (29). In addition, nineteen other metabolites were identified. The most active compounds were the two regioisomeric di-O-caffeoylquinic acid derivatives 26 and 29, with IC50 values of 5.93 and 5.20 μM, respectively. This is the first report of the α-glucosidase inhibitory activity of compounds 20, 26, and 29, and the findings support the important role of Eremanthus species as novel sources of new drugs and/or herbal remedies for treatment of type 2 diabetes.

  17. High-Resolution α-Glucosidase Inhibition Profiling Combined with HPLC-HRMS-SPE-NMR for Identification of Antidiabetic Compounds in Eremanthus crotonoides (Asteraceae

    Directory of Open Access Journals (Sweden)

    Eder Lana e Silva

    2016-06-01

    Full Text Available α-Glucosidase inhibitors decrease the cleavage- and absorption rate of monosaccharides from complex dietary carbohydrates, and represent therefore an important class of drugs for management of type 2 diabetes. In this study, a defatted ethyl acetate extract of Eremanthus crotonoides leaves with an inhibitory concentration (IC50 of 34.5 μg/mL towards α-glucosidase was investigated by high-resolution α-glucosidase inhibition profiling combined with HPLC-HRMS-SPE-NMR. This led to identification of six α-glucosidase inhibitors, namely quercetin (16, trans-tiliroside (17, luteolin (19, quercetin-3-methyl ether (20, 3,5-di-O-caffeoylquinic acid n-butyl ester (26 and 4,5-di-O-caffeoylquinic acid n-butyl ester (29. In addition, nineteen other metabolites were identified. The most active compounds were the two regioisomeric di-O-caffeoylquinic acid derivatives 26 and 29, with IC50 values of 5.93 and 5.20 μM, respectively. This is the first report of the α-glucosidase inhibitory activity of compounds 20, 26, and 29, and the findings support the important role of Eremanthus species as novel sources of new drugs and/or herbal remedies for treatment of type 2 diabetes.

  18. Heavy atom effects in the Paternò–Büchi reaction of pyrimidine derivatives with 4,4’-disubstituted benzophenones

    Directory of Open Access Journals (Sweden)

    Qin-Hua Song

    2011-01-01

    Full Text Available The regioselectivity and the photochemical efficiency were investigated in the Paternò–Büchi reaction of 1,3-dimethylthymine (DMT and 1,3-dimethyluracil (DMU with benzophenone (1b and some 4,4’-disubstituted derivatives (dimethoxy (1a, difluoro (1c, dichloro (1d, dibromo (1e and dicyano benzophenone (1f that gives rise to two regioisomeric oxetanes, 2 and 3. The regioselectivity (the ratio of 2/3 decreased gradually for both DMT/DMU photochemical systems from 1a to 1f. That is, a halogen atom as an electron-withdrawing group (EWG has a pronounced effect on the regioselectivity. However, the photochemical efficiency of the 1e systems did not show the expected increase, but decreased relative to systems with 1b. Temperature effects on the regioselectivity of 1b–e systems showed some interesting features for systems with heavy atoms (including the 1d and 1e systems, such as higher inversion temperatures, and an entropy-controlled regioselectively whereas the regioselectivity for two other systems (1b and 1c is enthalpy–entropy controlled. A heavy atom effect is suggested to be responsible for these unusual phenomena based on the triplet-diradical mechanism of the Paternò–Büchi reaction.

  19. Targeted chiral lipidomics analysis of bioactive eicosanoid lipids in cellular systems.

    Science.gov (United States)

    Lee, Seon Hwa; Blair, Ian A

    2009-07-31

    We have developed a targeted lipidomics approach that makes it possible to directly analyze chiral eicosanoid lipids generated in cellular systems. The eicosanoids, including prostaglandins (PGs), thromboxanes (TXs), leukotrienes (LTs) and alcohols (HETEs), have been implicated as potent lipid mediators of various biological processes. Enzymatic formations of eicosanoids are regioselective and enantioselective, whereas reactive oxygen species (ROS)-mediated formation proceeds with no stereoselectivity. To distinguish between enzymatic and non-enzymatic pathways of eicosanoid formation, it is necessary to resolve enantiomeric forms as well as regioisomers. High sensitivity is also required to analyze the eicosanoid lipids that are usually present as trace amounts (pM level) in biological fluids. A discovery of liquid chromatography-electron capture atmospheric pressure chemical ionization/mass spectrometry (LCECAPCI/MS) allows us to couple normal phase chiral chromatography without loss of sensitivity. Analytical specificity was obtained by the use of collision-induced dissociation (CID) and tandem MS (MS/MS). With combination of stable isotope dilution methodology, complex mixtures of regioisomeric and enantiomeric eicosanoids have been resolved and quantified in biological samples with high sensitivity and specificity. Targeted chiral lipidomics profiles of bioactive eicosanoid lipids obtained from various cell systems and their biological implications have been discussed.

  20. Indexing molecules with chemical graph identifiers.

    Science.gov (United States)

    Gregori-Puigjané, Elisabet; Garriga-Sust, Rut; Mestres, Jordi

    2011-09-01

    Fast and robust algorithms for indexing molecules have been historically considered strategic tools for the management and storage of large chemical libraries. This work introduces a modified and further extended version of the molecular equivalence number naming adaptation of the Morgan algorithm (J Chem Inf Comput Sci 2001, 41, 181-185) for the generation of a chemical graph identifier (CGI). This new version corrects for the collisions recognized in the original adaptation and includes the ability to deal with graph canonicalization, ensembles (salts), and isomerism (tautomerism, regioisomerism, optical isomerism, and geometrical isomerism) in a flexible manner. Validation of the current CGI implementation was performed on the open NCI database and the drug-like subset of the ZINC database containing 260,071 and 5,348,089 structures, respectively. The results were compared with those obtained with some of the most widely used indexing codes, such as the CACTVS hash code and the new InChIKey. The analyses emphasize the fact that compound management activities, like duplicate analysis of chemical libraries, are sensitive to the exact definition of compound uniqueness and thus still depend, to a minor extent, on the type and flexibility of the molecular index being used.

  1. Interconversion of nitrenes, azirenes, and diradicals: rearrangement of 3-isoquinolylnitrene to o-cyanophenylketenimine and 1-cyanoisoindole.

    Science.gov (United States)

    Vosswinkel, Michael; Lüerssen, Holger; Kvaskoff, David; Wentrup, Curt

    2009-02-06

    Photolysis of tetrazolo[1,5-b]isoquinoline/3-azidoisoquinoline 22T/22A generates 3-isoquinolylnitrene 23, which has been characterized together with a diradical species (25) by Ar matrix ESR spectroscopy. Photolysis at lambda > 300 nm generates azirene 24, characterized by IR spectroscopy, whereas further broad-band UV photolysis destroys the azirene to produce o-cyanophenylketenimine 17. The use of 15N-labeled tetrazole/azide 22T'/22A' demonstrates rapid equilibration of two regioisomeric 15N-labeled azirenes 24' and 24'' prior to formation of 17. Flash vacuum thermolysis (FVT) of 22T/22A affords 1-cyano-2H-isoindole 27 in quantitative yield. FVT of 15N-labeled tetrazole/azide 22T'/22A' causes scrambling of 15N label in the 1-cyano-2H-isoindole product. It is concluded that the interconversion of azirenes 24 takes place via the unobserved diazacycloheptatetraene/diazacycloheptatrienylidene 32/33, and that the rearrangement of azirene to ketenimine 17 and 1-cyanoisoindole 27 takes place via reversion to nitrene 23 followed by ring opening to diradical 25.

  2. How to identify and discriminate between the methyl quinates of chlorogenic acids by liquid chromatography-tandem mass spectrometry.

    Science.gov (United States)

    Jaiswal, Rakesh; Kuhnert, Nikolai

    2011-03-01

    The methyl esters of chlorogenic acids, methyl quinates, are widely distributed in plant materials and frequently appear as extraction artifacts in plant samples. This is the first time when liquid chromatography-tandem mass spectrometry methods have been used for the identification and characterization of the methyl quinates. For this purpose, methyl quinates of mono caffeoylquinic acids and mono feruloylquinic acids were synthesized as authentic standards. The methyl quinates of mono and diacyl chlorogenic acids have shown characteristic fragmentation pattern in their tandem mass spectra. MS(n + 1) spectra of the methyl quinates of diacyl chlorogenic acids were identical to MS(n) spectra of mono acyl derivatives. These quinates do not produce any methyl quinate peak at m/z 205 if compared with quinic acid peak at m/z 191 in negative ion mode. In the MS(n) spectra of these quinates, cinnamic acid part or cinnamoyl part was detected as a base peak in negative ion mode. The retention time, order of elution and fragmentation pattern were completely different if compared with LC-MS(n) methods developed for chlorogenic acids. These LC-MS(n) methods have been applied for the identification and regioisomeric characterization of the methyl quinates of chlorogenic acids in maté tea and woodruff (Galium odoratum). Two methyl caffeoylquinates (2 and 4) were identified as methyl 3-caffeoylquinate and methyl 5-caffeoylquinate.

  3. Identification and characterization of chlorogenic acids, chlorogenic acid glycosides and flavonoids from Lonicera henryi L. (Caprifoliaceae) leaves by LC-MSn.

    Science.gov (United States)

    Jaiswal, Rakesh; Müller, Heiko; Müller, Anja; Karar, Mohamed Gamaleldin Elsadig; Kuhnert, Nikolai

    2014-12-01

    The chlorogenic acids, chlorogenic acid glycosides and flavonoids of the leaves of Lonicera henryi L. (Caprifoliaceae) were investigated qualitatively by liquid chromatography tandem mass spectrometry. Thirty-one chlorogenic acids and their glycosides were detected and characterized to their regioisomeric level on the basis of their unique fragmentation pattern in the negative ion mode tandem MS spectra. All of them were extracted for the first time from this source and thirteen of them were not reported previously in nature. For the positive identification of chlorogenic acid glycosides by LC-MS(n), multiple reaction monitoring and targeted MS(n) experiments were performed. We have developed an LC-MS(n) method for the systematic identification of chlorogenic acid glycosides and were also able to discriminate between chlorogenic acids and their isobaric glycosides. It was also possible to discriminate between 5-O-(3'-O-caffeoyl glucosyl)quinic acid and 5-O-(4'-O-caffeoyl glucosyl)quinic acid by LC-MS(n). This method can be applied for the rapid and positive identification of chlorogenic acids and their glycosides in plant materials, food and beverages.

  4. A theoretical investigation on the regioselectivity of the intramolecular hetero Diels-Alder and 1,3-dipolar cycloaddition of 2-vinyloxybenzaldehyde derivatives

    Directory of Open Access Journals (Sweden)

    Hamzehloueian Mahshid

    2014-01-01

    Full Text Available The present study reports a systematic computational analysis of the two possible pathways, fused and bridged, for an intramolecular hetero Diels-Alder (IMHDA and an intramolecular 1,3-dipolar cycloaddition (IMDCA of 2-vinyloxybenzaldehyde derivatives. The potential energy surface analysis for both reactions is in agreement with experimental observations. The activation energies associated with the two regioisomeric channels in IMHDA reaction show that the bridged product is favored, although in IMDCA, the most stable TS results the fused product. The global electronic properties of fragments within each molecule were studied to discuss the reactivity patterns and charge transfer direction in the intramolecular processes. The asynchronicity of the bond formation and aromaticity of the optimized TSs in the Diels-Alder reaction as well as cycloaddition reaction were evaluated. Finally, 1H NMR chemical shifts of the possible regioisomers have been calculated using the GIAO method which of the most stable products are in agreement with the experimental data in the both reaction.

  5. N7-(carboxymethyl)guanine-Lithium Crystalline Complex: A Bioinspired Solid Electrolyte

    Science.gov (United States)

    Dutta, Dipak; Nagapradeep, N.; Zhu, Haijin; Forsyth, Maria; Verma, Sandeep; Bhattacharyya, Aninda J.

    2016-04-01

    Electrochemical device with components having direct significance to biological life processes is a potent futuristic strategy for the realization of all-round green and sustainable development. We present here synthesis design, structural analysis and ion transport of a novel solid organic electrolyte (G7Li), a compound reminiscent of ion channels, derived from regioisomeric N7-guanine-carboxylate conjugate and Li-ions. G7Li, with it’s in-built supply of Li+-ions, exhibited remarkably high lithium-ion transference number (= 0.75) and tunable room temperature ionic conductivity spanning three decades (≈10-7 to 10-3 Ω-1 cm-1) as a function of moisture content. The ionic conductivity show a distinct reversible transition around 80-100 °C, from a dual Li+ and H+ (100 °C). Systematic studies reveal a transition from water-assisted Li-ion transport to Li hopping-like mechanism involving guanine-Li coordination. While as-synthesized G7Li has potential in humidity sensors, the anhydrous G7Li is attractive for rechargeable batteries.

  6. Chemical reactivity predictions: use of data mining techniques for analyzing regioselective azidolysis of epoxides.

    Science.gov (United States)

    Borghini, Alice; Crotti, Paolo; Pietra, Daniele; Favero, Lucilla; Bianucci, Anna Maria

    2010-11-15

    Azidolysis of epoxides followed by reduction of the intermediate azido alcohols constitutes a valuable synthetic tool for the construction of beta-amino alcohols, an important chemical functionality occurring in many biologically active compounds of natural origin. However, depending on conditions under which the azidolysis is carried out, two regioisomeric products can be formed, as a consequence of the nucleophilic attack on both the oxirane carbon atoms. In this work, predictive models for quantitative structure-reactivity relationships were developed by means of multiple linear regression, k-nearest neighbor, locally weighted regression, and Gaussian Process regression algorithms. The specific nature of the problem at hand required the creation of appropriate new descriptors, able to properly reflect the most relevant features of molecular moieties directly involved in the opening process. The models so obtained are able to predict the regioselectivity of the azidolysis of epoxides promoted by sodium azide, in the presence of lithium perchlorate, on the basis of steric hindrance, and charge distribution of the substituents directly attached to the oxirane ring.

  7. Stereochemistry of substitution at trico-ordinate phosphorus

    DEFF Research Database (Denmark)

    Nielsen, John; Dahl, Otto

    1984-01-01

    and 31P) from reactant and product diastereoisomers have been assigned, and the stereo-chemistry of the substitution reactions have been determined by 31P n.m.r. monitoring. The outcome varies from complete inversion to complete lack of stereoselectivity. During the initial stages many of the non......-selective reactions proceed with predominant inversion, and most of the results may be interpreted by assuming that the actual substitution step occurs with inversion, and that the lack of stereoselectivity is due to competing isomerizations of products or reactants. Exceptions are certain reactions where the leaving......A series of reactions of ring-substituted 1,3,2-dioxaphospholanes, 1,3,2-oxazaphospholanes, 1,2-oxaphospholes, and phosphetanes bearing the leaving groups Cl, OR, or NR2 on phosphorus, with the nucleophiles HCl, MeO-, MeOH, PhOH, Me2NH, Et2NH, and [CH 2]5NH have been studied. N.m.r. signals (1H...

  8. Exo conformers of N-(pyridin-2-yl)- and N-(pyridin-3-yl)norbornene-5,6-dicarboximide crystals.

    Science.gov (United States)

    Vazquez-Vuelvas, Oscar F; Hernández-Madrigal, Julia V; Pineda-Contreras, Armando; Hernández-Ortega, Simón; Reyes-Martínez, Reyna; Morales-Morales, David

    2015-03-01

    Two isomeric pyridine-substituted norbornenedicarboximide derivatives, namely N-(pyridin-2-yl)-exo-norbornene-5,6-dicarboximide, (I), and N-(pyridin-3-yl)-exo-norbornene-5,6-dicarboximide, (II), both C(14)H(12)N(2)O(4), have been crystallized and their structures unequivocally determined by single-crystal X-ray diffraction. The molecules consist of norbornene moieties fused to a dicarboximide ring substituted at the N atom by either pyridin-2-yl or pyridin-3-yl in an anti configuration with respect to the double bond, thus affording exo isomers. In both compounds, the asymmetric unit consists of two independent molecules (Z' = 2). In compound (I), the pyridine rings of the two independent molecules adopt different conformations, i.e. syn and anti, with respect to the methylene bridge. The intermolecular contacts of (I) are dominated by C-H...O interactions. In contrast, in compound (II), the pyridine rings of both molecules have an anti conformation and the two independent molecules are linked by carbonyl-carbonyl interactions, as well as by C-H...O and C-H...N contacts.

  9. Synthesis, Antimycobacterial, Antifungal and Photosynthesis-Inhibiting Activity of Chlorinated N-phenylpyrazine-2-carboxamides †

    Directory of Open Access Journals (Sweden)

    Katarina Kralova

    2010-11-01

    Full Text Available A series of sixteen pyrazinamide analogues with the -CONH- linker connecting the pyrazine and benzene rings was synthesized by the condensation of chlorides of substituted pyrazinecarboxylic acids with ring-substituted (chlorine anilines. The prepared compounds were characterized and evaluated for their antimycobacterial and antifungal activity, and for their ability to inhibit photosynthetic electron transport (PET. 6-Chloro-N-(4-chlorophenylpyrazine-2-carboxamide manifested the highest activity against Mycobacterium tuberculosis strain H37Rv (65% inhibition at 6.25 μg/mL. The highest antifungal effect against Trichophyton mentagrophytes, the most susceptible fungal strain tested, was found for 6-chloro-5-tert-butyl-N-(3,4-dichlorophenylpyrazine-2-carboxamide (MIC = 62.5 μmol/L. 6-Chloro-5-tert-butyl-N-(4-chlorophenylpyrazine-2-carboxamide showed the highest PET inhibition in spinach chloroplasts (Spinacia oleracea L. chloroplasts (IC50 = 43.0 μmol/L. For all the compounds, the relationships between the lipophilicity and the chemical structure of the studied compounds as well as their structure-activity relationships are discussed.

  10. Design of aromatic-containing cell-penetrating peptide mimics with structurally modified π electronics.

    Science.gov (United States)

    deRonde, Brittany M; Birke, Alexander; Tew, Gregory N

    2015-02-09

    Cell-penetrating peptides (CPPs) and their synthetic mimics (CPPMs) represent a class of molecules that facilitate the intracellular delivery of various cargo. Previous studies indicated that the presence of aromatic functionalities improved CPPM activity. Given that aromatic functionalities play prominent roles in membrane biology and participate in various π interactions, we explored whether these interactions could be optimized for improved CPPM activity. CPPMs were synthesized by ring-opening metathesis polymerization by using monomers that contained aromatic rings substituted with electron-donating and electron-withdrawing groups and covered an electrostatic potential range from -29.69 to +15.57 kcal mol(-1) . These groups altered the quadrupole moments of the aromatic systems and were used to test if such structural modifications changed CPPM activity. CPPMs were added to dye-loaded vesicles and the release of carboxyfluorescein was monitored as a function of polymer concentration. Changes in the effective polymer concentration to release 50% of the dye (effective concentration, EC50 ) were monitored. Results from this assay showed that the strength of the electron-donating and electron-withdrawing groups incorporated in the CPPMs did not alter polymer EC50 values or activity. This suggests that other design parameters may have a stronger impact on CPPM activity. In addition, these results indicate that a wide range of aromatic groups can be incorporated without negatively impacting polymer activity.

  11. [Liver damage caused by drugs].

    Science.gov (United States)

    Strohmeyer, G; Weik, C

    1999-05-01

    The liver has a central role in the metabolism of many drugs, since this organ is the main site of biotransformation of endo- and xenobiotics. Water-soluble drugs have a small volume of distribution and can be eliminated unchanged in the urine. By contrast, lipid-soluble drugs have a larger volume of distribution and require conversion to water-soluble metabolites for their elimination in urine or bile. The liver with its specific receptors, transporters and enzymes is responsible for the uptake, transformation and excretion of the lipophilic drugs. While most of the drugs are transformed into stable metabolites, other drugs form reactive, potentially toxic, metabolites producing liver cell damage. Liver injury caused by drugs may mimic almost any kind of liver disease. Clinical findings are gastrointestinal symptoms with nausea, vomiting and abdominal pain, cholestatic liver injury with jaundice and pruritus of severe inflammatory and cirrhotic liver damage with signs of liver failure, encephalopathy and cerebral edema. The morphological changes vary from hepatitis, cholestasis, fatty liver, granulomatous hepatitis, peri-/portal inflammation, to fibrosis with cirrhotic alterations and vascular lesions and tumors. The most commonly used drugs causing severe liver injury are discussed in detail. These are anabolics, oral contraceptives, antituberculous and antifungal agents, nonsteroidal anti-inflammatory drugs, ring substituted amphetamins ("designer drugs"), antiarrhythmics and antibiotics.

  12. Amide resonance and FT-IR spectra of some β-lactam derivatives: application of resolution enhancement procedures in Fourier space

    Science.gov (United States)

    Gil, M.; Plumet, J.; Iza, N.; Morcillo, J.

    1988-05-01

    Fourier Transform infrared (FT-IR) spectra of five 4-acyl-β-lactam derivatives in three organic solvents (carbon tetrachloride, benzene and chloroform) have been registered. Nominal spectral resolution was 1 cm -1 and a Happ-Genzel function was used to apodize the interferograms. Fourier self-deconvolutions were done using standard software based on the algorithm of Kauppinen (1981). The digitalized FT-IR spectra were converted into second and fourth derivatives in Fourier domain using a standard software package supplied for the purpose and based on the technique developed by the N.R.C.C. group. The inherent enhancement resolution of Fourier self-deconvolution and derivatives in Fourier Space have permitted resolution of the characteristic "amide I" bands of the β-lactam ring. The ν(CO) band splitting in the "amide I" region is due to solvent and ring substitution influences on amide resonance and not to H-bonding association. Simultaneous application of both apparent resolution enhancement procedures has allowed us to identify true bands and mathematical artifacts.

  13. Identification of Selective ERRγ Inverse Agonists

    Directory of Open Access Journals (Sweden)

    Jina Kim

    2016-01-01

    Full Text Available GSK5182 (4 is currently one of the lead compounds for the development of estrogen-related receptor gamma (ERRγ inverse agonists. Here, we report the design, synthesis, pharmacological and in vitro absorption, distribution, metabolism, excretion, toxicity (ADMET properties of a series of compounds related to 4. Starting from 4, a series of analogs were structurally modified and their ERRγ inverse agonist activity was measured. A key pharmacophore feature of this novel class of ligands is the introduction of a heterocyclic group for A-ring substitution in the core scaffold. Among the tested compounds, several of them are potent ERRγ inverse agonists as determined by binding and functional assays. The most promising compound, 15g, had excellent binding selectivity over related subtypes (IC50 = 0.44, >10, >10, and 10 μM at the ERRγ, ERRα, ERRβ, and ERα subtypes, respectively. Compound 15g also resulted in 95% transcriptional repression at a concentration of 10 μM, while still maintaining an acceptable in vitro ADMET profile. This novel class of ERRγ inverse agonists shows promise in the development of drugs targeting ERRγ-related diseases.

  14. Solvent dependent photophysical properties of dimethoxy curcumin

    Science.gov (United States)

    Barik, Atanu; Indira Priyadarsini, K.

    2013-03-01

    Dimethoxy curcumin (DMC) is a methylated derivative of curcumin. In order to know the effect of ring substitution on photophysical properties of curcumin, steady state absorption and fluorescence spectra of DMC were recorded in organic solvents with different polarity and compared with those of curcumin. The absorption and fluorescence spectra of DMC, like curcumin, are strongly dependent on solvent polarity and the maxima of DMC showed red shift with increase in solvent polarity function (Δf), but the above effect is prominently observed in case of fluorescence maxima. From the dependence of Stokes' shift on solvent polarity function the difference between the excited state and ground state dipole moment was estimated as 4.9 D. Fluorescence quantum yield (ϕf) and fluorescence lifetime (τf) of DMC were also measured in different solvents at room temperature. The results indicated that with increasing solvent polarity, ϕf increased linearly, which has been accounted for the decrease in non-radiative rate by intersystem crossing (ISC) processes.

  15. Substituted N-Phenylpyrazine-2-carboxamides, Their Synthesis and Evaluation as Herbicides and Abiotic Elicitors

    Directory of Open Access Journals (Sweden)

    Katarína Kráľová

    2007-12-01

    Full Text Available The condensation of substituted pyrazine-2-carboxylic acid chlorides with ring-substituted anilines yielded five substituted pyrazine-2-carboxylic acid amides. Thesynthesis, and analytical, lipophilicity and biological data of the newly synthesizedcompounds are presented in this paper. The photosynthesis inhibition, antialgal activityand the effect of a series of pyrazine derivatives as abiotic elicitors on the accumulation offlavonoids in a callus culture of Ononis arvensis (L. were investigated. The most activeinhibitor of the oxygen evolution rate in spinach chloroplasts was 6-chloro-pyrazine-2-carboxylic acid (3-iodo-4-methylphenyl-amide (2, IC50 = 51.0 μmol·L-1. The highestreduction of chlorophyll content in Chlorella vulgaris was found for 5-tert-butyl-N-(4-chloro-3-methylphenyl-pyrazine-2-carboxamide (3, IC50 = 44.0 μmol·L-1. The maximalflavonoid production (about 900% was reached after a twelve-hour elicitation processwith 6-chloropyrazine-2-carboxylic acid (3-iodo-4-methylphenyl-amide (2.

  16. Structure-Based Design of Novel Pyrimido[4,5-c]pyridazine Derivatives as Dihydropteroate Synthase Inhibitors with Increased Affinity

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Ying; Hammoudeh, Dalia; Yun, Mi-Kyung; Qi, Jianjun; White, Stephen W.; Lee, Richard E. (Tennessee-HSC); (SJCH)

    2012-05-29

    Dihydropteroate synthase (DHPS) is the validated drug target for sulfonamide antimicrobial therapy. However, due to widespread drug resistance and poor tolerance, the use of sulfonamide antibiotics is now limited. The pterin binding pocket in DHPS is highly conserved and is distinct from the sulfonamide binding site. It therefore represents an attractive alternative target for the design of novel antibacterial agents. We previously carried out the structural characterization of a known pyridazine inhibitor in the Bacillus anthracis DHPS pterin site and identified a number of unfavorable interactions that appear to compromise binding. With this structural information, a series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines were designed to improve binding affinity. Most importantly, the N-methyl ring substitution was removed to improve binding within the pterin pocket, and the length of the side chain carboxylic acid was optimized to fully engage the pyrophosphate binding site. These inhibitors were synthesized and evaluated by an enzyme activity assay, X-ray crystallography, isothermal calorimetry, and surface plasmon resonance to obtain a comprehensive understanding of the binding interactions from structural, kinetic, and thermodynamic perspectives. This study clearly demonstrates that compounds lacking the N-methyl substitution exhibit increased inhibition of DHPS, but the beneficial effects of optimizing the side chain length are less apparent.

  17. Benzo[1,2-b:4,5-b’]dithiophene-Pyrido[3,4-b]pyrazine Small-Molecule Donors for Bulk Heterojunction Solar Cells

    KAUST Repository

    Wolf, Jannic Sebastian

    2016-01-22

    We report on the synthesis, material properties and BHJ solar cell characteristics of a set of π-conjugated small-molecule (SM) donors composed of benzo[1,2-b:4,5-b′]dithiophene (BDT) and pyrido[3,4-b]pyrazine (PP) units – examining the perspectives of alkyl-substituted PP acceptor motifs in SM designs. In these systems (SM1-4), both the type of side chains derived from the PP motifs and the presence of ring-substituents on BDT critically impact (i) molecular packing, and (ii) thin-film morphologies and charge transport in BHJ solar cells. With the appropriate side-chain pattern, the ring-substituted analogue SM4 stands out: achieving efficiencies of ca. 6.5% with PC71BM, and fine-scale morphologies comparable to those obtained with some of the best-performing polymer donors in BHJ solar cells. 1H-1H DQ-SQ NMR analyses are used to examine the distinct self-assembly pattern of SM4, expected to factor into the development of the BHJ morphology.

  18. The acute effects of 3,4-methylenedioxymethamphetamine on oxidative stress in rat brain

    Directory of Open Access Journals (Sweden)

    Simić Ivan

    2008-01-01

    Full Text Available Introduction Oxidative stress and oxygen free radicals are thought to play an important role in acute effects of a number of neurotoxic processes. 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy, a ring substituted amphetamine derivate, has attracted a great deal of media attention in recent years due to its widespread abuse as recreational drug by the young generation. The aim of the present study was to evaluate the acute effects of 3,4-methylenedioxymethamphetamine on oxidative stress parameters (index of lipid peroxidation - ILP, superoxide radicals O2-, superoxide dismutase - SOD and glutathione - GSH in frontal cortex, striatum and hippocampus in Wistar rats. Materials and methods The study included 40 male Wistar rats (200-250 g, housed 4 per cage having free access to food and water. MDMA was dissolved in distillated water and administered peroraly at 5, 10, 20 or 40 mg/kg. 8 hours following MDMA, the rats were killed by decapitation, their brains were rapidly removed and the brain structures were dissected out on ice and analyzed biochemically. Results Acute peroral administration of a single dose (5, 10, 20 and 40 mg/kg resulted in increase of ILP, O2-, SOD and decrease of GSH. Conclusion The results obtained in the present study suggest that oxidative stress plays a crucial role in MDMA-induced neurotoxicity and that the mechanism of MDMA neurotoxycity may vary between brain regions.

  19. Testing of some azo dyes and their reduction products for mutagenicity using Salmonella typhimurium TA 1538.

    Science.gov (United States)

    Garner, R C; Nutman, C A

    1977-07-01

    A series of ten azo dyes as well as various single ring aromatic amines substituted on the benzene ring were tested for bacterial mutagenicity with Salmonella typhimurium TA 1538 using a soft-agar overlay method. Two dyes, sudan 2 and chrysoidin induced mutation but only in the presence of a rat liver preparation. Chrysoidin was the more active. Testing of its reduction products, aniline and 1,2,4-triaminobenzene showed a liver metabolite of the latter compound could be responsible for the mutagenic effect, having a comparable mutagenicity with 1,2-diamino-4-nitro-benzene, one of the mutagenic constituents of hair dyes. Structure-activity studies on a series of ring-substituted anilines indicated that mutagenic activity required at least two positions to be substituted with either amino or nitro groups, or one of each. The bacteria as well as the liver enzyme preparation may partake in the activation of these chemicals. The correlation between mutagenicity and carcinogenicity for this group of compounds is discussed.

  20. Applying medicinal chemistry strategies to understand odorant discrimination.

    Science.gov (United States)

    Poivet, Erwan; Peterlin, Zita; Tahirova, Narmin; Xu, Lu; Altomare, Clara; Paria, Anne; Zou, Dong-Jing; Firestein, Stuart

    2016-04-04

    Associating an odorant's chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants.

  1. Abundant and stable char residues in soils: implications for soil fertility and carbon sequestration.

    Science.gov (United States)

    Mao, J-D; Johnson, R L; Lehmann, J; Olk, D C; Neves, E G; Thompson, M L; Schmidt-Rohr, K

    2012-09-04

    Large-scale soil application of biochar may enhance soil fertility, increasing crop production for the growing human population, while also sequestering atmospheric carbon. But reaching these beneficial outcomes requires an understanding of the relationships among biochar's structure, stability, and contribution to soil fertility. Using quantitative (13)C nuclear magnetic resonance (NMR) spectroscopy, we show that Terra Preta soils (fertile anthropogenic dark earths in Amazonia that were enriched with char >800 years ago) consist predominantly of char residues composed of ~6 fused aromatic rings substituted by COO(-) groups that significantly increase the soils' cation-exchange capacity and thus the retention of plant nutrients. We also show that highly productive, grassland-derived soils in the U.S. (Mollisols) contain char (generated by presettlement fires) that is structurally comparable to char in the Terra Preta soils and much more abundant than previously thought (~40-50% of organic C). Our findings indicate that these oxidized char residues represent a particularly stable, abundant, and fertility-enhancing form of soil organic matter.

  2. Tuning color variation in grape anthocyanins at the molecular scale.

    Science.gov (United States)

    Rustioni, Laura; Di Meo, Florent; Guillaume, Maxime; Failla, Osvaldo; Trouillas, Patrick

    2013-12-15

    Anthocyanins are the main grape pigments. Due to their aromatic cyclic arrangements, they are able to absorb the radiation in the low energy range of the visible spectrum. In the fruit of Vitis vinifera L., the five main anthocyanidins (cyanidin, peonidin, delphinidin, petunidin and malvidin) are present as 3-O-glucosides, as well as their acetyl, p-coumaroyl and caffeoyl ester forms. Despite the huge number of experimental studies dedicated to the anthocyanin profile analysis of grapes and wines, the complete theoretical elucidation of the optical properties of grape anthocyanins is missing. The present work carried out this task through quantum chemistry calculations based on time-dependent density functional theory (TD-DFT), compared to experimental spectra. The differences in visible absorption spectra between the most common grape anthocyanins were rationalized according to B-ring substitution, glucosylation and esterification. A particular attention was given to the intra-molecular copigmentation effect, demonstrating the existence of an intra-molecular charge transfer excited state for the p-coumaroyl and caffeoyl ester forms.

  3. Structural and functional characterization of solute binding proteins for aromatic compounds derived from lignin: p-coumaric acid and related aromatic acids.

    Science.gov (United States)

    Tan, Kemin; Chang, Changsoo; Cuff, Marianne; Osipiuk, Jerzy; Landorf, Elizabeth; Mack, Jamey C; Zerbs, Sarah; Joachimiak, Andrzej; Collart, Frank R

    2013-10-01

    Lignin comprises 15-25% of plant biomass and represents a major environmental carbon source for utilization by soil microorganisms. Access to this energy resource requires the action of fungal and bacterial enzymes to break down the lignin polymer into a complex assortment of aromatic compounds that can be transported into the cells. To improve our understanding of the utilization of lignin by microorganisms, we characterized the molecular properties of solute binding proteins of ATP-binding cassette transporter proteins that interact with these compounds. A combination of functional screens and structural studies characterized the binding specificity of the solute binding proteins for aromatic compounds derived from lignin such as p-coumarate, 3-phenylpropionic acid and compounds with more complex ring substitutions. A ligand screen based on thermal stabilization identified several binding protein clusters that exhibit preferences based on the size or number of aromatic ring substituents. Multiple X-ray crystal structures of protein-ligand complexes for these clusters identified the molecular basis of the binding specificity for the lignin-derived aromatic compounds. The screens and structural data provide new functional assignments for these solute-binding proteins which can be used to infer their transport specificity. This knowledge of the functional roles and molecular binding specificity of these proteins will support the identification of the specific enzymes and regulatory proteins of peripheral pathways that funnel these compounds to central metabolic pathways and will improve the predictive power of sequence-based functional annotation methods for this family of proteins.

  4. Nitrogen Doped Carbon Nanotubes from Organometallic Compounds: A Review

    Directory of Open Access Journals (Sweden)

    Neil J. Coville

    2010-03-01

    Full Text Available Nitrogen doped carbon nanotubes (N-CNTs have become a topic of increased importance in the study of carbonaceous materials. This arises from the physical and chemical properties that are created when N is embedded in a CNT. These properties include modified chemical reactivity and modified conductivity and mechanical properties. A range of methodologies have been devised to synthesize N-CNTs. One of the procedures uses a floating catalyst in which an organometallic complex is decomposed in the gas phase in the presence of a nitrogen containing reactant to give N-CNTs. Most studies have been limited to ferrocene, ring substituted ferrocene and Fe(CO5. This review covers the synthesis (and properties of N-CNTs and other shaped carbon nanomaterials (SCNMs produced using organometallic complexes. It summarizes the effects that physical parameters such as temperature, pressure, gas flow rates, type and concentration of N source etc. have on the N-CNT type, size and yields as well as the nitrogen content incorporated into the tubes that are produced from organometallic complexes. Proposed growth models for N-CNT synthesis are also reported.

  5. Anion Binding of One-, Two-, and Three-Armed Thiourea Receptors Examined via Photoelectron Spectroscopy and Quantum Computations

    Energy Technology Data Exchange (ETDEWEB)

    Beletskiy, Evgeny V.; Wang, Xue-Bin; Kass, Steven R.

    2016-10-27

    A benzene ring substituted with 1–3 thiourea containing arms (1–3) were examined by photoelectron spectroscopy and density functional theory computations. Their conjugate bases and chloride, acetate and dihydrogen phosphate anion clusters are reported. The resulting vertical and adiabatic detachment energies span from 3.93 – 5.82 eV (VDE) and 3.65 – 5.10 (ADE) for the deprotonated species and 4.88 – 5.97 eV (VDE) and 4.45 – 5.60 eV (ADE) for the anion complexes. These results reveal the stabilizing effects of multiple hydrogen bonds and anionic host-guest interactions in the gas phase. Previously measured equilibrium binding constants in aqueous dimethyl sulfoxide for all three thioureas (Org. Biolmol. Chem. 2015, 13, 2170-2176) are compared to the present results and cooperative binding is uniformly observed in the gas phase but only for one case (i.e., 3 • H2PO4–) in solution.

  6. Applying medicinal chemistry strategies to understand odorant discrimination

    Science.gov (United States)

    Poivet, Erwan; Peterlin, Zita; Tahirova, Narmin; Xu, Lu; Altomare, Clara; Paria, Anne; Zou, Dong-Jing; Firestein, Stuart

    2016-01-01

    Associating an odorant's chemical structure with its percept is a long-standing challenge. One hindrance may come from the adoption of the organic chemistry scheme of molecular description and classification. Chemists classify molecules according to characteristics that are useful in synthesis or isolation, but which may be of little importance to a biological sensory system. Accordingly, we look to medicinal chemistry, which emphasizes biological function over chemical form, in an attempt to discern which among the many molecular features are most important for odour discrimination. Here we use medicinal chemistry concepts to assemble a panel of molecules to test how heteroaromatic ring substitution of the benzene ring will change the odour percept of acetophenone. This work allows us to describe an extensive rule in odorant detection by mammalian olfactory receptors. Whereas organic chemistry would have predicted the ring size and composition to be key features, our work reveals that the topological polar surface area is the key feature for the discrimination of these odorants. PMID:27040654

  7. Influence of Lipophilicity on the Toxicity of Bisphenol A and Phthalates to Aquatic Organisms.

    Science.gov (United States)

    Mathieu-Denoncourt, Justine; Wallace, Sarah J; de Solla, Shane R; Langlois, Valerie S

    2016-07-01

    Bisphenol A (BPA) and phthalates are among the most popular plasticizers used today and have been reported ubiquitously in surface water, ground water, and sediment. For aquatic organisms, BPA was the most toxic (96 h LC50s) to aquatic invertebrates (0.96-2.70 mg/L) and less toxic to fish (6.8-17.9 mg/L). The toxicity of BPA to amphibians differed among developmental stages, with embryos having an LC50 of 4.6-6.8 mg/L and juveniles 0.50-1.4 mg/L. The toxicity of phthalates is affected by aromatic ring substitution, alkyl chain length, and metabolism. The toxicity (96 h LC50s) of phthalates was similar to aquatic invertebrates (0.46-377 mg/L) and fish (0.48-121 mg/L). In general, the toxicity of phthalates appears to be highest around a log KOW of 6, which corresponds to the highest potential for bioconcentration and bioaccumulation. In conclusion, the lipophilicity of BPA and phthalates influence their toxicity to aquatic species.

  8. Photochemical generation, isomerization, and oxygenation of stilbene cation radicals

    Energy Technology Data Exchange (ETDEWEB)

    Lewis, F.D.; Bedell, A.M.; Dykstra, R.E.; Elbert, J.E. (Northwestern Univ., Evanston, IL (USA)); Gould, I.R.; Farid, S. (Eastman Kodak Co., Rochester, NY (USA))

    1990-10-24

    The cation radicals of cis- and trans-stilbene and several of their ring-substituted derivatives have been generated in solution directly by means of pulsed-laser-induced electron transfer to singlet cyanoanthracenes or indirectly via electron transfer from biphenyl to the singlet cyanoanthracene followed by secondary electron transfer from the stilbenes to the biphenyl cation radical. Transient absorption spectra of the cis- and trans-stilbene cation radicals generated by secondary electron transfer are similar to those previously obtained in 77 K matrices. Quantum yields for radical ion-pair cage escape have been measured for direct electron transfer from the stilbenes to three neutral and one charged singlet acceptor. These values increase as the ion-pair energy increases due to decreased rate constants for radical ion-pair return electron transfer, in accord with the predictions of Marcus theory for highly exergonic electron transfer. Cage-escape efficiencies are larger for trans- vs cis-stilbene cation radicals, possibly due to the greater extent of charge delocalization in the planar trans vs nonpolar cis cation radicals. Cage-escape stilbene cation radicals can initiate a concentration-dependent one way cis- {yields} trans-stilbene isomerization reaction.

  9. Changes in CYP1A2 activity in humans after 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) administration using caffeine as a probe drug.

    Science.gov (United States)

    Yubero-Lahoz, Samanta; Pardo, Ricardo; Farre, Magí; Mathuna, Brian Ó; Torrens, Marta; Mustata, Cristina; Perez-Mañá, Clara; Langohr, Klaus; Carbó, Marcel Lí; de la Torre, Rafael

    2012-01-01

    3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is a ring-substituted amphetamine widely used for recreational purposes. MDMA is predominantly O-demethylenated in humans by cytochrome P450 (CYP) 2D6, and is also a potent mechanism-based inhibitor of the enzyme. After assessing the inhibition and recovery of CYP2D6 in a previous study, the aim of this work was to study in humans the activity of CYP1A2 in vivo after CYP2D6 had been inhibited by MDMA, using caffeine as a probe drug. Twelve male and nine female recreational MDMA users were included. In session 1, 100 mg of caffeine was given at 0 h. In session 2, a 1.5 mg/kg MDMA dose (range 75-100 mg) was given at 0 h followed by a 100 mg dose of caffeine 4 h later. Aliquots of plasma were assayed for caffeine (137X) and paraxanthine (17X) and statistically significant differences were assessed with a one-way ANOVA. There were significant gender differences at basal condition, which persisted after MDMA administration. CYP1A2 activity was higher in both genders after drug administration, with an increase in 40% in females and 20% in males. Results show an increase in CYP1A2 activity when CYP2D6 is inhibited by MDMA in both genders, being more pronounced in females.

  10. Antiproliferative and Pro-Apoptotic Effect of Novel Nitro-Substituted Hydroxynaphthanilides on Human Cancer Cell Lines

    Directory of Open Access Journals (Sweden)

    Tereza Kauerova

    2016-07-01

    Full Text Available Ring-substituted hydroxynaphthanilides are considered as cyclic analogues of salicylanilides, compounds possessing a wide range of pharmacological activities, including promising anticancer properties. The aim of this study was to evaluate the potential anticancer effect of novel nitro-substituted hydroxynaphthanilides with a special focus on structure-activity relationships. The antiproliferative effect was assessed by Water Soluble Tetrazolium Salts-1 (WST-1 assay, and cytotoxicity was evaluated via dye exclusion test. Flow cytometry was used for cell cycle analysis and detection of apoptosis using Annexin V-FITC/PI assay. Protein expression was estimated by Western blotting. Our data indicate that the potential to cause the antiproliferative effect increases with the shift of the nitro substituent from the ortho- to the para-position. The most potent compounds, 3-hydroxy-N-(3-nitrophenylnaphthalene-2-carboxamide (2, and 2-hydroxy-N-(4-nitrophenyl-naphthalene-1-carboxamide (6 showed antiproliferative activity against THP-1 and MCF-7 cancer cells without affecting the proliferation of 3T3-L1 non-tumour cells. Compounds 2 and 6 induced the accumulation of THP-1 and MCF-7 cells in G1 phase associated with the downregulation of cyclin E1 protein levels, while the levels of cyclin B1 were not affected. Moreover, compound 2 was found to exert the pro-apoptotic effect on the THP-1 cells. These results suggest that hydroxynaphthanilides might represent a potential model structure for the development of novel anticancer agents.

  11. Syntheses of a library of molecules on the marine natural product ianthelliformisamines platform and their biological evaluation.

    Science.gov (United States)

    Khan, Faiz Ahmed; Ahmad, Saeed; Kodipelli, Naveena; Shivange, Gururaj; Anindya, Roy

    2014-06-21

    Ianthelliformisamines A-C are a novel class of bromotyrosine-derived antibacterial agents isolated recently from the marine sponge Suberea ianthelliformis. We have synthesized ianthelliformisamines A-C straightforwardly by the condensation of (E)-3-(3,5-dibromo-4-methoxyphenyl)acrylic acid and the corresponding Boc-protected polyamine followed by Boc-deprotection with TFA. Further, using this reaction protocol, a library of their analogues (39 analogues) has been synthesized by employing 3-phenylacrylic acid derivatives and Boc-protected polyamine chains through various combinations of these two fragments differing in phenyl ring substitution, double bond geometry or chain length of the central spacer of the polyamine chain (shown in red color). All the synthesized compounds (ianthelliformisamines A-C and their analogues) were screened for antibacterial activity against both Gram-negative (Escherichia coli) and Gram-positive (Staphylococcus aureus) strains. All synthetic analogues of ianthelliformisamine A showed bacterial growth inhibition against both strains (Escherichia coli and Staphylococcus aureus), having MIC values in the range of 117.8-0.10 μM, while none of the synthetic analogues of ianthelliformisamine C as well as the parent compound showed any detectable antibacterial activity. Interestingly, some of the synthetic analogues of ianthelliformisamines A and B exerted a bactericidal effect against both E. coli and S. aureus strains, decreasing viable bacterial count by 99% at concentrations as low as 2 × MIC.

  12. Enzymatic synthesis of enantiopure alpha- and beta-amino acids by phenylalanine aminomutase-catalysed amination of cinnamic acid derivatives.

    Science.gov (United States)

    Wu, Bian; Szymanski, Wiktor; Wietzes, Piet; de Wildeman, Stefaan; Poelarends, Gerrit J; Feringa, Ben L; Janssen, Dick B

    2009-01-26

    The phenylalanine aminomutase (PAM) from Taxus chinensis catalyses the conversion of alpha-phenylalanine to beta-phenylalanine, an important step in the biosynthesis of the N-benzoyl phenylisoserinoyl side-chain of the anticancer drug taxol. Mechanistic studies on PAM have suggested that (E)-cinnamic acid is an intermediate in the mutase reaction and that it can be released from the enzyme's active site. Here we describe a novel synthetic strategy that is based on the finding that ring-substituted (E)-cinnamic acids can serve as a substrate in PAM-catalysed ammonia addition reactions for the biocatalytic production of several important beta-amino acids. The enzyme has a broad substrate range and a high enantioselectivity with cinnamic acid derivatives; this allows the synthesis of several non-natural aromatic alpha- and beta-amino acids in excellent enantiomeric excess (ee >99 %). The internal 5-methylene-3,5-dihydroimidazol-4-one (MIO) cofactor is essential for the PAM-catalysed amination reactions. The regioselectivity of amination reactions was influenced by the nature of the ring substituent.

  13. Discovery of dihydroxylated 2,4-diphenyl-6-thiophen-2-yl-pyridine as a non-intercalative DNA-binding topoisomerase II-specific catalytic inhibitor.

    Science.gov (United States)

    Jun, Kyu-Yeon; Kwon, Hanbyeol; Park, So-Eun; Lee, Eunyoung; Karki, Radha; Thapa, Pritam; Lee, Jun-Ho; Lee, Eung-Seok; Kwon, Youngjoo

    2014-06-10

    We describe our rationale for designing specific catalytic inhibitors of topoisomerase II (topo II) over topoisomerase I (topo I). Based on 3D-QSAR studies of previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives, 9 novel dihydroxylated 2,4-diphenyl-6-thiophen-2-yl pyridine compounds were designed, synthesized, and their biological activities were evaluated. These compounds have 2-thienyl ring substituted on the R(3) group on the pyridine ring and they all showed excellent specificity toward topo II compared to topo I. In vitro experiments were performed for compound 13 to determine the mechanism of action for this series of compounds. Compound 13 inhibited topoisomerase II specifically by non-intercalative binding to DNA and did not stabilize enzyme-cleavable DNA complex. Compound 13 efficiently inhibited cell viability, cell migration, and induced G1 arrest. Also from 3D-QSAR studies, the results were compared with other previously published dihydroxylated 2,4-diphenyl-6-aryl pyridine derivatives to explain the structure-activity relationships.

  14. Electron-Deficient Dihydroindaceno-Dithiophene Regioisomers for n-Type Organic Field-Effect Transistors.

    Science.gov (United States)

    Peltier, Jean-David; Heinrich, Benoît; Donnio, Bertrand; Rault-Berthelot, Joëlle; Jacques, Emmanuel; Poriel, Cyril

    2017-03-08

    In this work, we wish to report the first member of a new family of organic semiconductors constructed on a meta dihydroindacenodithiophene core, that is, 2,2'-(2,8-dihexyl-4,6-dihydro-s-indaceno[1,2-b:7,6-b']dithiophene-4,6-diylidene)dimalononitrile (called meta-IDT(═C(CN)2)2). The properties of this molecule were studied in detail through a structure-properties relationship study with its regioisomer, that is, 2,2'-(2,7-dihexyl-4,9-dihydro-s-indaceno[1,2-b:5,6-b']dithiophene-4,9-diylidene)dimalononitrile (para-IDT(═C(CN)2)2) (see isomer structures in blue in Chart 2). The influence of the bridge functionalization was also investigated by comparison with their diketone analogues meta-IDT(═O)2 and para-IDT(═O)2. This study sheds light on the impact of regioisomerism on the electronic properties at the molecular level (electrochemistry, absorption spectroscopy, molecular modeling) and also on the supramolecular arrangement, and finally on the organic field-effect transistors (OFET) performances and stabilities. The significant effect of self-assembled monolayers of 4-(dimethylamino)benzenethiol grafted on the gold drain and source electrodes or of the use of flexible substrate (polyethylene naphtalate) instead of glass on the OFET performances and stabilities are also reported. In the light of these results (maximum mobility reaching 7.1 × 10(-2) cm(2) V(-1) cm(-1), high IDon/IDoff of 2.3 × 10(7), and subthreshold swing of 1.2 V/dec), we believe that the present OFETs can be further used to construct electronic circuits.

  15. Synthesis and Physicochemical Characterization of the Process-Related Impurities of Olmesartan Medoxomil. Do 5-(Biphenyl-2-yl-1-triphenylmethyltetrazole Intermediates in Sartan Syntheses Exist?

    Directory of Open Access Journals (Sweden)

    Iwona Dams

    2015-12-01

    Full Text Available During the process development for multigram-scale synthesis of olmesartan medoxomil (OM, two principal regioisomeric process-related impurities were observed along with the final active pharmaceutical ingredient (API. The impurities were identified as N-1- and N-2-(5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl derivatives of OM. Both compounds, of which N-2 isomer of olmesartan dimedoxomil is a novel impurity of OM, were synthesized and fully characterized by differential scanning calorimetry (DSC, infrared spectroscopy (IR, nuclear magnetic resonance spectroscopy (NMR and high-resolution mass spectrometry/electrospray ionization (HRMS/ESI. Their 1H, 13C and 15N nuclear magnetic resonance signals were fully assigned. The molecular structures of N-triphenylmethylolmesartan ethyl (N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, the key intermediates in OM synthesis, were solved and refined using single-crystal X-ray diffraction (SCXRD. The SCXRD study revealed that N-tritylated intermediates of OM exist exclusively as one of the two possible regioisomers. In molecular structures of these regioisomers, the trityl substituent is attached to the N-2 nitrogen atom of the tetrazole ring, and not to the N-1 nitrogen, as has been widely reported up to the present. This finding indicates that the reported structural formula of N-tritylolmesartan ethyl and N-tritylolmesartan medoxomil, as well as their systematic chemical names, must be revised. The careful analysis of literature spectroscopic data for other sartan intermediates and their analogs with 5-(biphenyl-2-yltetrazole moiety showed that they also exist exclusively as N-2-trityl regioisomers.

  16. Effects of alkyl chain length and substituent pattern of fullerene bis-adducts on film structures and photovoltaic properties of bulk heterojunction solar cells.

    Science.gov (United States)

    Tao, Ran; Umeyama, Tomokazu; Kurotobi, Kei; Imahori, Hiroshi

    2014-10-08

    A series of alkoxycarbonyl-substituted dihydronaphthyl-based [60]fullerene bis-adduct derivatives (denoted as C2BA, C4BA, and C6BA with the alkyl chain of ethyl, n-butyl, and n-hexyl, respectively) have been synthesized to investigate the effects of alkyl chain length and substituent pattern of fullerene bis-adducts on the film structures and photovoltaic properties of bulk heterojunction polymer solar cells. The shorter alkyl chain length caused lower solubility of the fullerene bis-adducts (C6BA > C4BA > C2BA), thereby resulting in the increased separation difficulty of respective bis-adduct isomers. The device performance based on poly(3-hexylthiophene) (P3HT) and the fullerene bis-adduct regioisomer mixtures was enhanced by shortening the alkyl chain length. When using the regioisomerically separated fullerene bis-adducts, the devices based on trans-2 and a mixture of trans-4 and e of C4BA exhibited the highest power conversion efficiencies of ca. 2.4%, which are considerably higher than those of the C6BA counterparts (ca. 1.4%) and the C4BA regioisomer mixture (1.10%). The film morphologies as well as electron mobilities of the P3HT:bis-adduct blend films were found to affect the photovoltaic properties considerably. These results reveal that the alkyl chain length and substituent pattern of fullerene bis-adducts significantly influence the photovoltaic properties as well as the film structures of bulk heterojunction solar cells.

  17. Benzothiazoles with tunable electron-withdrawing strength and reverse polarity: a route to triphenylamine-based chromophores with enhanced two-photon absorption.

    Science.gov (United States)

    Hrobárik, Peter; Hrobáriková, Veronika; Sigmundová, Ivica; Zahradník, Pavol; Fakis, Mihalis; Polyzos, Ioannis; Persephonis, Peter

    2011-11-01

    A series of dipolar and octupolar triphenylamine-derived dyes containing a benzothiazole positioned in the matched or mismatched fashion have been designed and synthesized via palladium-catalyzed Sonogashira cross-coupling reactions. Linear and nonlinear optical properties of the designed molecules were tuned by an additional electron-withdrawing group (EWG) and by changing the relative positions of the donor and acceptor substituents on the heterocyclic ring. This allowed us to examine the effect of positional isomerism and extend the structure-property relationships useful in the engineering of novel heteroaromatic-based systems with enhanced two-photon absorption (TPA). The TPA cross-sections (δ(TPA)) in the target compounds dramatically increased with the branching of the triphenylamine core and with the strength of the auxiliary acceptor. In addition, a change from the commonly used polarity in push-pull benzothiazoles to a reverse one has been revealed as a particularly useful strategy (regioisomeric control) for enhancing TPA cross-sections and shifting the absorption and emission maxima to longer wavelengths. The maximum TPA cross-sections of the star-shaped three-branched triphenylamines are ∼500-2300 GM in the near-infrared region (740-810 nm); thereby the molecular weight normalized δ(TPA)/MW values of the best performing dyes within the series (2.0-2.4 GM·g(-1)·mol) are comparable to those of the most efficient TPA chromophores reported to date. The large TPA cross-sections combined with high emission quantum yields and large Stokes shifts make these compounds excellent candidates for various TPA applications, including two-photon fluorescence microscopy.

  18. Synthesis, Anti-Breast Cancer Activity, and Molecular Docking Study of a New Group of Acetylenic Quinolinesulfonamide Derivatives

    Directory of Open Access Journals (Sweden)

    Krzysztof Marciniec

    2017-02-01

    Full Text Available In this study, a series of regioisomeric acetylenic sulfamoylquinolines are designed, synthesized, and tested in vitro for their antiproliferative activity against three human breast cacer cell lines (T47D, MCF-7, and MDA-MB-231 and a human normal fibroblast (HFF-1 by 4-[3-(4-iodophenyl-2-(4-nitrophenyl-2H-5-tetrazolio]-1,3-benzene disulfonate (WST-1 assay. The antiproliferative activity of the tested acetylenic quinolinesulfonamides is comparable to that of cisplatin. The bioassay results demonstrate that most of the tested compounds show potent antitumor activities, and that some compounds exhibit better effects than the positive control cisplatin against various cancer cell lines. Among these compounds, 4-(3-propynylthio-7-[N-methyl-N-(3-propynylsulfamoyl]quinoline shows significant antiprolierative activity against T47D cells with IC50 values of 0.07 µM. In addition, 2-(3-Propynylthio-6-[N-methyl-N-(3-propynylsulfa-moyl]quinoline and 2-(3-propynylseleno-6-[N-methyl-N-(3-propynylsulfamoyl]quinoline display highly effective atitumor activity against MDA-MB-231 cells, with IC50 values of 0.09 and 0.50 µM, respectively. Furthermore, most of the tested compounds show a weak cytotoxic effect against the normal HFF-1 cell line. Additionally, in order to suggest a mechanism of action for their activity, all compounds are docked into the binding site of two human cytochrome P450 (CYP isoenzymes. These data indicate that some of the title compounds display significant cytotoxic activity, possibly targeting the CYPs pathways.

  19. Isomerism in benzyl-DOTA derived bifunctional chelators: implications for molecular imaging.

    Science.gov (United States)

    Payne, Katherine M; Woods, Mark

    2015-02-18

    The bifunctional chelator IB-DOTA has found use in a range of biomedical applications given its ability to chelate many metal ions, but in particular the lanthanide(III) ions. Gd(3+) in particular is of interest in the development of new molecular imaging agents for MRI and is highly suitable for chelation by IB-DOTA. Given the long-term instability of the aryl isothiocyanate functional group we have used the more stable nitro derivative (NB-DOTA) to conduct a follow-up study of some of our previous work on the coordination chemistry of chelates of these BFCs. Using a combination of NMR and HPLC to study the Eu(3+) and Yb(3+) chelates of NB-DOTA, we have demonstrated that this ligand will produce two discrete regioisomeric chelates at the point at which the metal ion is introduced into the BFC. These regioisomers are defined by the position of the benzylic substituent on the macrocyclic ring: adopting an equatorial position either at the corner or the side of the [3333] ring conformation. These regioisomers are incapable of interconversion and are distinct, separate structures with different SAP/TSAP ratios. The side isomer exhibits an increased population of the TSAP isomer, pointing to more rapid water exchange kinetics in this regioisomer. This has potential ramifications for the use of these two regioisomers of Gd(3+)-BFC chelates in MRI applications. We have also found that, remarkably, there is little or no freedom of rotation about the first single bond extending from the macrocyclic ring to the benzylic substituent. Since this is the linkage through which the chelate is conjugated to the remainder of the molecular imaging probe, this result implies that there may be reduced local rotation of the Gd(3+) chelate within a molecular imaging probe. This implies that this type of BFC could exhibit higher relaxivities than other types of BFC.

  20. Substituted Pyrazinecarboxamides: Synthesis and Biological Evaluation

    Directory of Open Access Journals (Sweden)

    Katarina Kralova

    2006-03-01

    Full Text Available Condensation of the corresponding chlorides of some substituted pyrazine-2-carboxylic acids (pyrazine-2-carboxylic acid, 6-chloropyrazine-2-carboxylic acid, 5-tert-butylpyrazine-2-carboxylic acid or 5-tert-butyl-6-chloropyrazine-2-carboxylic acid withvarious ring-substituted aminothiazoles or anilines yielded a series of amides. Thesyntheses, analytical and spectroscopic data of thirty newly prepared compounds arepresented. Structure-activity relationships between the chemical structures and the anti-mycobacterial, antifungal and photosynthesis-inhibiting activity of the evaluatedcompounds are discussed. 3,5-Bromo-4-hydroxyphenyl derivatives of substitutedpyrazinecarboxylic acid, 16-18, have shown the highest activity against Mycobacteriumtuberculosis H37Rv (54-72% inhibition. The highest antifungal effect againstTrichophyton mentagrophytes, the most susceptible fungal strain tested, was found for5-tert-butyl-6-chloro-N-(4-methyl-1,3-thiazol-2-ylpyrazine-2-carboxamide (8, MIC =31.25 μmol·mL-1. The most active inhibitors of oxygen evolution rate in spinachMolecules 2006, 11 243 chloroplasts were the compounds 5-tert-butyl-6-chloro-N-(5-bromo-2-hydroxyphenyl- pyrazine-2-carboxamide (27, IC50 = 41.9 μmol·L-1 and 5-tert-butyl-6-chloro-N-(1,3- thiazol-2-yl-pyrazine-2-carboxamide (4, IC50 = 49.5 μmol·L-1.

  1. HPLC-ESI-MS/MS of brain neurotransmitter modulator lobeline and related piperidine alkaloids in Lobelia inflata L.

    Science.gov (United States)

    Kursinszki, László; Szőke, Éva

    2015-05-01

    There is a renewed interest in lobelia alkaloids because of their activity on the central nervous system. Lobeline, the most active of them, a nicotinic receptor ligand and neurotransmitter transporter inhibitor, is a candidate pharmacotherapy for metamphetamine abuse. In the present work, high-performance liquid chromatography coupled with electrospray ionization tandem mass spectrometry in positive ion mode was used for investigating the alkaloid profile in Lobelia inflata L. Chromatographic separations were achieved on a Gemini C6-phenyl reversed-phase column providing good peak shape and improved selectivity. Being mostly 2,6-disubstituted piperidines, lobelia alkaloids presented abundant [M + H](+) ions with typical fragmentation. Identification was possible from a few specific ions, especially those resulting from excision of one of the substituents. Based on fragmentation pattern of lobeline as reference compound, 52 alkaloids were identified in the aqueous methanolic extract of L. inflata in contrast to the previously known some 20. Structural variability of these alkaloids identified arises basically from their substituents which can be phenyl-2-ketoethyl- or phenyl-2-hydroxyethyl units as well as their methyl-, ethyl- or propyl- homologues attached in different combinations. Several propyl homologue lobelia alkaloids and five hydroxypiperidine derivatives were found in the plant at the first time. In addition to 8-O-esters of 2-monosubstituted piperidine alkaloids previously reported by us in L. inflata, a 3-hydroxy-3-phenylpropanoic acid ester of hydroxyallosedamine ring-substituted was also identified as a new natural product. High-performance liquid chromatography-electrospray ionization tandem mass spectrometry can be successfully applied to Lobeliacae plant samples in the routine screening for new and known bioactive constituents, quality control of the crude drug, lobelia herba, alkaloid production studies, breeding and chemotaxonomy.

  2. Morphology and biochemistry of non-glandular trichomes in Cistus salvifolius L. leaves growing in extreme habitats of the Mediterranean basin.

    Science.gov (United States)

    Tattini, M; Matteini, P; Saracini, E; Traversi, M L; Giordano, C; Agati, G

    2007-05-01

    Here the functional roles of stellate and dendritic trichomes in Cistus salvifolius L leaves were studied by analysing i) both leaf surface and trichome morphology using scanning electron and light microscopy; and ii) the composition and localisation of polyphenols by coupling liquid chromatography with fluorescence spectroscopy and fluorescence microimaging. Red-coloured compounds were detected in the stalk cells and the channel in the trichome arm, and appeared to be released at the tip end of the trichome branch. We identified such metabolites as ellagitannins, namely punicalagin and two galloyl derivatives of punicalagin. These ellagitannins accounted for 4.3 % of leaf dry weight and their concentration in the leaf leachate averaged 289.4 mg L (-1). The trichome arms exhibited an appreciable orange-red autofluorescence (centred at 620 nm) when excited with UV light (at 365 nm) or emitted in the yellow waveband (peak centred at 566 nm) when stained with the Naturstoff reagent, and excited at 488 nm. The fluorescence signatures of the trichome arms were consistent with the presence of mono-hydroxy B-ring substituted flavonoids, which were identified as the mono- and di-coumaroyl derivative of a kaempferol 3-O-glycoside. Our data may provide some insights on the functional roles of stellate and dendritic trichomes in the response mechanisms of C. salvifolius to Mediterranean-type climate, based upon (i) the potential effect of released ellagitannins on the soil nitrogen dynamic and (ii) the ability of acylated kaempferol 3-O-glycosides to effectively absorb both the UV-B and UV-A wavelengths.

  3. Chronic tolerance to recreational MDMA (3,4-methylenedioxymethamphetamine) or Ecstasy.

    Science.gov (United States)

    Parrott, A C

    2005-01-01

    This review of chronic tolerance to MDMA (3,4-methylenedioxymetamphetamine) covers the empirical data on dosage escalation, reduced subjective efficacy and bingeing in recreational Ecstasy users. Novice users generally take a single Ecstasy tablet, regular users typically take 2-3 tablets, whereas the most experienced users may take 10-25 tablets in a single session. Reduced subjective efficacy following repeated usage is typically described, with many users subjectively reporting the development of tolerance. Intensive self-administration or bingeing is often noted by experienced users. This can comprise 'stacking' on several tablets together, and 'boosting' on successive doses over an extended period. Some experienced users snort Ecstasy powder nasally, whereas a small minority inject MDMA. Chronic tolerance and bingeing are statistically linked to higher rates of drug-related psychobiological problems. In terms of underlying mechanisms, neuroadaptive processes are certainly involved, but there is a paucity of evidence on hepatic and behavioural mechanisms. Further studies specifically designed to investigate chronic tolerance, involving low intermittent dose regimens, are required. Most animal research has involved intensive MDMA dosing regimens designed to engender serotonergic neurotoxicity, and this may comprise another underlying mechanism. If distal serotonin axon terminal loss was also developing in recreational users, it may help to explain why reducing subjective efficacy, dosage escalation and increasing psychobiological problems often develop in parallel. In conclusion, there is extensive evidence for chronic pharmacodynamic tolerance to recreational Ecstasy/MDMA, but the underlying mechanisms are currently unclear. Several traditional processes are probably involved, but one of the possible causes is a novel mechanism largely unique to the ring substituted amphetamine derivatives, namely serotonergic neurotoxicity.

  4. Vesicular monoamine transporter 2 and the acute and long-term response to 3,4-(±)-methylenedioxymethamphetamine.

    Science.gov (United States)

    Lizarraga, Lucina E; Cholanians, Aram B; Phan, Andy V; Herndon, Joseph M; Lau, Serrine S; Monks, Terrence J

    2015-01-01

    3,4-(±)-Methylenedioxymethamphetamine (MDMA, Ecstasy) is a ring-substituted amphetamine derivative with potent psychostimulant properties. The neuropharmacological effects of MDMA are biphasic in nature, initially causing synaptic monoamine release, primarily of serotonin (5-HT). Conversely, the long-term effects of MDMA manifest as prolonged depletions in 5-HT, and reductions in 5-HT reuptake transporter (SERT), indicative of serotonergic neurotoxicity. MDMA-induced 5-HT efflux relies upon disruption of vesicular monoamine storage, which increases cytosolic 5-HT concentrations available for release via a carrier-mediated mechanism. The vesicular monoamine transporter 2 (VMAT2) is responsible for packaging monoamine neurotransmitters into cytosolic vesicles. Thus, VMAT2 is a molecular target for a number of psychostimulant drugs, including methamphetamine and MDMA. We investigated the effects of depressed VMAT2 activity on the adverse responses to MDMA, via reversible inhibition of the VMAT2 protein with Ro4-1284. A single dose of MDMA (20 mg/kg, subcutaneous) induced significant hyperthermia in rats. Ro4-1284 (10 mg/kg, intraperitoneal) pretreatment prevented the thermogenic effects of MDMA, instead causing a transient decrease in body temperature. MDMA-treated rats exhibited marked increases in horizontal velocity and rearing behavior. In the presence of Ro4-1284, MDMA-mediated horizontal hyperlocomotion was delayed and attenuated, whereas rearing activity was abolished. Finally, Ro4-1284 prevented deficits in 5-HT content in rat cortex and striatum, and reduced depletions in striatal SERT staining, 7 days after MDMA administration. In summary, acute inhibition of VMAT2 by Ro4-1284 protected against MDMA-mediated hyperthermia, hyperactivity, and serotonergic neurotoxicity. The data suggest the involvement of VMAT2 in the thermoregulatory, behavioral, and neurotoxic effects of MDMA.

  5. Co-crystals of 3-deoxy-3-fluoro-α-D-glucopyranose and 3-deoxy-3-fluoro-β-D-glucopyranose.

    Science.gov (United States)

    Zhang, Wenhui; Oliver, Allen G; Serianni, Anthony S

    2010-11-01

    3-Deoxy-3-fluoro-D-glucopyranose crystallizes from acetone to give a unit cell containing two crystallographically independent molecules. One of these molecules (at site A) is structurally homogeneous and corresponds to 3-deoxy-3-fluoro-β-D-glucopyranose, C(6)H(11)FO(5), (I). The second molecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3-deoxy-3-fluoro-α-D-glucopyranose, (II); treatment of the diffraction data using partial-occupancy oxygen at the anomeric center gave a high-quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of α- and β-anomers at site B appears to be accommodated in the lattice because hydrogen-bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. Cremer-Pople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [θ((I)) = 3.85 (15)° and θ((II)) = 6.35 (16)°], but the general direction of distortion is similar in both structures [ϕ((I)) = 67 (2)° (B(C1,C4)) and ϕ((II)) = 26.0 (15)° ((C3)TB(C1)); B = boat conformation and TB = twist-boat conformation]. The exocyclic hydroxymethyl (-CH(2)OH) conformation is gg (gauche-gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, deoxy and fluorine-substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns.

  6. Electrospray ionization tandem mass spectrometric and electron impact mass spectrometric characterization of mycosporine-like amino acids.

    Science.gov (United States)

    Whitehead, Kenia; Hedges, John I

    2003-01-01

    Positive-ion mass spectral fragmentations of seven mycosporine-like amino acids (MAAs) are reported and discussed. The MAAs studied are small compounds composed of a cycloheximine ring substituted with amino acid or amino alcohol units. Techniques used include electron impact (EI) and electrospray ionization (ESI) with tandem mass spectrometry (MS/MS). ESI-MS/MS showed unusual small radical losses, generally resulting from the loss of a methyl group with the exception of shinorine and porphyra for which the initial losses were 30 and 44 Da, respectively. As expected from structural similarities, porphyra, shinorine and palythinol displayed similar fragmentation patterns, while palythenic acid and palythene fragmented in a similar manner. Overall, the ESI-MS/MS fragmentations at m/z <200 exhibited a distinctive pattern for all seven MAAs with characteristic ions at m/z 137, 168, 186, and 197 or 199. Several ions were observed for each of the MAAs analyzed, and together provide a useful and potentially diagnostic pattern for identification of MAAs and as an aid in structure elucidation of novel MAAs. For GC/EI-MS analysis, trimethylsilyl (TMS) derivatives were made. The EI-MS fragmentation patterns of TMS-MAAs showed many features typical of TMS-derivatized alpha-amines. The precursor TMS-MAA ion was not detected, but a [M-90](+ radical) ion was the highest-mass intense peak observed for palythine, palythinol and shinorine, while palythene gave a [M-116](+ radical) ion. Besides determining the number of acidic hydrogens, EI-MS of TMS-derivatized MAAs will aid in structure elucidation of novel MAAs. Copyright 2003 John Wiley & Sons, Ltd.

  7. Spectral properties and reactivity of diarylmethanol radical cations in aqueous solution. Evidence for intramolecular charge resonance.

    Science.gov (United States)

    Bietti, Massimo; Lanzalunga, Osvaldo

    2002-04-19

    Spectral properties and reactivities of ring-methoxylated diarylmethane and diarylmethanol radical cations, generated in aqueous solution by pulse and gamma-radiolysis and by the one-electron chemical oxidant potassium 12-tungstocobalt(III)ate, have been studied. The radical cations display three bands in the UV, visible, and vis-NIR regions of the spectrum. The vis-NIR band is assigned to an intramolecular charge resonance interaction (CR) between the neutral donor and charged acceptor rings, as indicated by the observation that the relative intensity of the vis-NIR band compared to that of the UV and visible bands does not increase with increasing substrate concentration and that the position and intensity of this band is influenced by the ring-substitution pattern. In acidic solution (pH = 4), monomethoxylated diarylmethanol radical cations 1a.(+ -)1e.(+) decay by C(alpha)-H deprotonation [k = (1.7-1.9) x 10(4)s(-1)] through the intermediacy of a ketyl radical, which is further oxidized in the reaction medium to give the corresponding benzophenones, as evidenced by both time-resolved spectroscopic and product studies. With the dimethoxylated radical cation 2.(+), C(alpha)-H deprotonation is instead significantly slower (k = 6.7 x 10(2)s(-1)). In basic solution, 1a.(+)-1e.(+) undergo (-)OH-induced deprotonation from the alpha-OH group with k(OH.)approximately equal to 1.4 x 10(10)M(-1)s(-1), leading to a ketyl radical anion, which is oxidized in the reaction medium to the corresponding benzophenone.

  8. Polymer Main-Chain Substitution Effects on the Efficiency of Nonfullerene BHJ Solar Cells

    KAUST Repository

    Firdaus, Yuliar

    2017-07-21

    “Nonfullerene” acceptors are proving effective in bulk heterojunction (BHJ) solar cells when paired with selected polymer donors. However, the principles that guide the selection of adequate polymer donors for high-efficiency BHJ solar cells with nonfullerene acceptors remain a matter of some debate and, while polymer main-chain substitutions may have a direct influence on the donor–acceptor interplay, those effects should be examined and correlated with BHJ device performance patterns. This report examines a set of wide-bandgap polymer donor analogues composed of benzo[1,2-b:4,5-b′]dithiophene (BDT), and thienyl ([2H]T) or 3,4-difluorothiophene ([2F]T) motifs, and their BHJ device performance pattern with the nonfullerene acceptor “ITIC”. Studies show that the fluorine- and ring-substituted derivative PBDT(T)[2F]T largely outperforms its other two polymer donor counterparts, reaching power conversion efficiencies as high as 9.8%. Combining several characterization techniques, the gradual device performance improvements observed on swapping PBDT[2H]T for PBDT[2F]T, and then for PBDT(T)[2F]T, are found to result from (i) notably improved charge generation and collection efficiencies (estimated as ≈60%, 80%, and 90%, respectively), and (ii) reduced geminate recombination (being suppressed from ≈30%, 25% to 10%) and bimolecular recombination (inferred from recombination rate constant comparisons). These examinations will have broader implications for further studies on the optimization of BHJ solar cell efficiencies with polymer donors and a wider range of nonfullerene acceptors.

  9. Photoinduced electron transfer interaction of anthraquinones with aniline quenchers: Influence of methyl substitution in aniline donors

    Science.gov (United States)

    Sivakumar, V.; Ponnamma, Deepalekshmi; Hussein, Yasser H. A.

    2017-02-01

    Photoinduced electron transfer between triplet state of 9,10-anthraquinone (AQ) and its two derivatives: 2-chloro-9,10-anthraquinone (CAQ) and sodium anthraquinone-2-sulfonate (AQS) and ground state aniline (AN) and its dimethyl substitutions: 2,3-dimethylaniline (2,3-DMA), 2,6-dimethylaniline (2,6-DMA), 3,5-dimethylaniline (3,5-DMA) and N,N-dimethylaniline (N,N-DMA) is studied using nanosecond laser flash photolysis at room temperature. Detection of radical bands of quinone anions and aniline cations along with their formation and/or decay kinetics are used to confirm the electron transfer (ET) process. In MeCN medium, AN quenches the triplet state of CAQ (CAQT) but not the triplets AQT or AQST. However in aqueous medium, AN quenches AQST and forms radical ion pair. All the DMAs can react through ET with all the triplet quinones at different degrees of efficiency in MeCN medium. Noticeably, the ring substituted DMAs are less efficient in electron donation to AQT or AQST while the N,N-DMA shows high efficiency in donating electron to all triplet quinones in MeCN medium. Charge distribution of donor molecules, in MeCN medium is calculated using density functional theory (DFT), and shows an enhancement of electron density of the ring of N,N-DMA, making it an ideal electron donor for ET studies compared to other DMAs. This systematic selection and usage of anilines with electrochemically tunable quinones can be viewed as a working model of donor-acceptor system that can be utilized in photoinduced ET applications.

  10. Lanthanide amidinates and guanidinates: from laboratory curiosities to efficient homogeneous catalysts and precursors for rare-earth oxide thin films.

    Science.gov (United States)

    Edelmann, Frank T

    2009-08-01

    For decades, the organometallic chemistry of the rare earth elements was largely dominated by the cyclopentadienyl ligand and its ring-substituted derivatives. A hot topic in current organolanthanide chemistry is the search for alternative ligand sets which are able to satisfy the coordination requirements of the large lanthanide cations. Among the most successful approaches in this field is the use of amidinate ligands of the general type [RC(NR')(2)](-) (R = H, alkyl, aryl; R' = alkyl, cycloalkyl, aryl, SiMe(3)) which can be regarded as steric cyclopentadienyl equivalents. Closely related are the guanidinate anions of the general type [R(2)NC(NR')(2)](-) (R = alkyl, SiMe(3); R' = alkyl, cycloalkyl, aryl, SiMe(3)). Two amidinate or guanidinate ligands can coordinate to a lanthanide ion to form a metallocene-like coordination environment which allows the isolation and characterization of stable though very reactive amide, alkyl, and hydride species. Mono- and trisubstituted lanthanide amidinate and guanidinate complexes are also readily available. Various rare earth amidinates and guanidinates have turned out to be very efficient homogeneous catalysts e.g. for ring-opening polymerization reactions. Moreover, certain alkyl-substituted lanthanide tris(amidinates) and tris(guanidinates) were found to be highly volatile and could thus be promising precursors for ALD (= Atomic Layer Deposition) and MOCVD (= Metal-Organic Chemical Vapor Deposition) processes in materials science and nanotechnology. This tutorial review covers the success story of lanthanide amidinates and guanidinates and their transition from mere laboratory curiosities to efficient homogeneous catalysts as well as ALD and MOCVD precursors.

  11. UV-vis spectroscopy and colorimetric models for detecting anthocyanin-metal complexes in plants: An overview of in vitro and in vivo techniques.

    Science.gov (United States)

    Fedenko, Volodymyr S; Shemet, Sergiy A; Landi, Marco

    2017-02-10

    Although anthocyanin (ACN) biosynthesis is one of the best studied pathways of secondary metabolism in plants, the possible physiological and ecological role(s) of these pigments continue to intrigue scientists. Like other dihydroxy B-ring substituted flavonoids, ACNs have an ability to bind metal and metalloid ions, a property that has been exploited for a variety of purposes. For example, the metal binding ability may be used to stabilize ACNs from plant food sources, or to modify their colors for using them as food colorants. The complexation of metals with cyanidin derivatives can also be used as a simple, sensitive, cheap, and rapid method for determination concentrations of several metals in biological and environmental samples using UV-vis spectroscopy. Far less information is available on the ecological significance of ACN-metal complexes in plant-environment interactions. Metalloanthocyanins (protocyanin, nemophilin, commelinin, protodelphin, cyanosalvianin) are involved in the copigmentation phenomenon that leads to blue-pigmented petals, which may facilitate specific plant-pollinator interactions. ACN-metal formation and compartmentation into the vacuole has also been proposed to be part of an orchestrated detoxification mechanism in plants which experience metal/metalloid excess. However, investigations into ACN-metal interactions in plant biology may be limited because of the complexity of the analytical techniques required. To address this concern, here we describe simple methods for the detection of ACN-metal both in vitro and in vivo using UV-vis spectroscopy and colorimetric models. In particular, the use of UV-vis spectra, difference absorption spectra, and colorimetry techniques will be described for in vitro determination of ACN-metal features, whereas reflectance spectroscopy and colorimetric parameters related to CIE L(*)a(*)b(*) and CIE XYZ systems will be detailed for in vivo analyses. In this way, we hope to make this high-informative tool

  12. Selectively N-protected enantiopure 2,5-disubstituted piperazines: avoiding the pitfalls in solid-phase Fukuyama-Mitsunobu cyclizations.

    Science.gov (United States)

    Ottesen, Lars K; Olsen, Christian A; Witt, Matthias; Jaroszewski, Jerzy W; Franzyk, Henrik

    2009-01-01

    An efficient solid-phase route to ring-substituted piperazines from O-linked resin-bound (S)-aziridine-2-methanol is described. Regioselective microwave-assisted aminolysis followed by intramolecular Fukuyama-Mitsunobu cyclization constitute the key features of the protocol. Simple piperazines and diazepanes were readily obtained without preceding N-protection of the acyclic intermediate, whereas attempts to extend this protocol to chiral 2,5-disubstituted piperazines failed. Modifications encompassing N-carbamoylation prior to ring-closure were therefore investigated. However, standard carbamoylating agents, for example, Fmoc-Cl and Alloc-Cl tended to give bis-protected by-products. Thus, novel microwave-assisted solid-phase N-protection procedures were developed for efficient introduction of Fmoc, Boc and Alloc groups. The subsequent cyclization proceeded in moderate to excellent yields depending on the bulk of the side chain and type of N-protecting group. This protocol readily provided novel cis- and trans-2,5-disubstituted piperazines displaying a variety of N-protecting group patterns after further on-resin manipulations. Also, unexpected by-products obtained during these optimization studies were identified and characterized. This includes nosylated ureas arising from an alternative cyclization pathway. Finally, post-cleavage oxidation gave access to the Fmoc/Boc-protected alpha-amino acid as well as the corresponding aldehyde. The chiral piperazines described in this work will enable construction of combinatorial libraries with a higher chemical diversity compared to those containing simple N,N'-difunctionalized piperazines, often present in drug-like compounds.

  13. Novel substrates and inhibitors of peptidylglycine alpha-amidating monooxygenase.

    Science.gov (United States)

    Katopodis, A G; May, S W

    1990-05-15

    Peptidylglycine alpha-amidating monooxygenase (PAM, EC 1.14.17.3) catalyzes the formation of alpha-amidated peptides from their glycine-extended precursors, thus playing a key role in the processing of peptide neurohormones. We now report that PAM readily catalyzes three alternate monooxygenase reactions--sulfoxidation, amine N-dealkylation, and O-dealkylation. Thus, (4-nitrobenzyl)thioacetic acid is converted to the analogous sulfoxide, N-(4-nitrobenzyl)glycine is converted to 4-nitrobenzylamine and glyoxylate, and [(4-nitrobenzyl)oxy]acetic acid is converted to 4-nitrobenzyl alcohol and glyoxylate. All these new activities display the characteristics expected for the normal PAM-catalyzed reductive oxygenation pathway and produce an equimolar amount of glyoxylate together with the heteroatom-containing dealkylation products. The ester [(4-methoxybenzoyl)oxy]acetic acid is not a PAM substrate, but is instead a good competitive inhibitor (KI = 0.48 mM). In addition, we report that the olefinic substrate analogues trans-benzoylacrylic acid and 4-phenyl-3-butenoic acid are potent time-dependent inactivators of PAM, with inactivation exhibiting the characteristics expected for mechanism-based inhibition. Monoethyl fumarate is also a time-dependent inactivator of PAM. Finally, we introduce several small non-peptide substrates for PAM by demonstrating that PAM catalyzes the transformation of hippuric acid and several ring-substituted derivatives to the corresponding benzamides and glyoxylic acid, with the most facile substrate of this class being 4-nitrohippuric acid. These compounds are the smallest amide substrates yet reported for PAM, and it is thus apparent that only the minimal structure of an acylglycine is required for PAM-catalyzed oxygenative amidation.

  14. Nonsteroidal selective androgen receptor modulators enhance female sexual motivation.

    Science.gov (United States)

    Jones, Amanda; Hwang, Dong Jin; Duke, Charles B; He, Yali; Siddam, Anjaiah; Miller, Duane D; Dalton, James T

    2010-08-01

    Women experience a decline in estrogen and androgen levels after natural or surgically induced menopause, effects that are associated with a loss of sexual desire and bone mineral density. Studies in our laboratories have shown the beneficial effects of selective androgen receptor modulators (SARMs) in the treatment of osteoporosis and muscle wasting in animal models. A series of S-3-(phenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-trifluoromethyl-phenyl)-propionamide analogs was synthesized to evaluate the effects of B-ring substitutions on in vitro and in vivo pharmacologic activity, especially female sexual motivation. The androgen receptor (AR) relative binding affinities ranged from 0.1 to 26.5% (relative to dihydrotestosterone) and demonstrated a range of agonist activity at 100 nM. In vivo pharmacologic activity was first assessed by using male rats. Structural modifications to the B-ring significantly affected the selectivity of the SARMs, demonstrating that single-atom substitutions can dramatically and unexpectedly influence activity in androgenic (i.e., prostate) and anabolic (i.e., muscle) tissues. (S)-N-(4-cyano-3-trifluoromethyl-phenyl)-3-(3-fluoro,4-chlorophenoxy)-2-hydroxy-2-methyl-propanamide (S-23) displayed full agonist activity in androgenic and anabolic tissues; however, the remaining SARMs were more prostate-sparing, selectively maintaining the size of the levator ani muscle in castrated rats. The partner-preference paradigm was used to evaluate the effects of SARMs on female sexual motivation. With the exception of two four-halo substituted analogs, the SARMs increased sexual motivation in ovariectomized rats, with potency and efficacy comparable with testosterone propionate. These results indicate that the AR is important in regulating female libido given the nonaromatizable nature of SARMs and it could be a superior alternative to steroidal testosterone preparations in the treatment of hypoactive sexual desire disorder.

  15. Identification of regioisomers of methylated kaempferol and quercetin by ultra high performance liquid chromatography quadrupole time-of-flight (UHPLC–QTOF) tandem mass spectrometry combined with diagnostic fragmentation pattern analysis

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Chengying; Lv, Haipeng; Zhang, Xinzhong; Chen, Zongmao; Shi, Jiang [Tea Research Institute, Chinese Academy of Agricultural Sciences, 9 Meiling South Road, Hangzhou, Zhejiang 310008 (China); Lu, Meiling, E-mail: meilinglu@hotmail.com [Chemical Analysis Group, Agilent Technologies, No. 3 Wangjing North Road, Chaoyang Distr., Beijing 100102 (China); Lin, Zhi, E-mail: linz@mail.tricaas.com [Tea Research Institute, Chinese Academy of Agricultural Sciences, 9 Meiling South Road, Hangzhou, Zhejiang 310008 (China)

    2013-09-17

    Highlights: •Found methane elimination is position-specific for methylated flavonols. •Found retro Diels–Alder fragments retained methoxy at original ring of flavonols. •Proposed a diagnostic pattern for discriminating regioisomers of flavonols. •Identified the specificity of three novel flavonol O-methyltransferases. •Identified six biologically active compounds and four new compounds. -- Abstract: The O-methylation of active flavonoids can enhance their antiallergic, anticancerous, and cardioprotective effects depending on the methylation position. Thus, it is biologically and pharmacologically important to differentiate methylated flavonoid regioisomers. In this study, we examined the regioisomers of methylated kaempferol and quercetin using ultra high performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry. The methyl groups on the flavonoids can generally be cleaved as methyl radicals in a position-independent manner. We found that methyl groups can be cleaved as methane. If there are protons adjacent the methoxy on the flavonol rings, intra-molecule proton transfer can occur via collision-induced dissociation, and one molecule of methane can then be eliminated. The remaining charged fragment ([M+H−CH{sub 4}]{sup +}) reflects the adjacent structure and is specific to the methoxy position. Furthermore, the retro Diels–Alder (RDA) fragmentation of methylated flavonols can generate fragments with the methoxy at the original methylated ring. Combining the position-specific [M+H−CH{sub 4}]{sup +} fragment with the RDA fragments provides a diagnostic pattern for rapidly identifying methylated regioisomeric flavonols. Along with their retention behaviour, we have successfully identified ten regioisomers of methylated kaempferol and quercetin, which include six compounds previously reported in plants and shown to be biologically active. The developed approach is sensitive, rapid, reliable, and requires few standard

  16. Hydrolytic Cleavage Products of Globin Adducts in Urine as Possible Biomarkers of Cumulative Dose: Proof of Concept Using Styrene Oxide as a Model Adduct-Forming Compound.

    Science.gov (United States)

    Mráz, Jaroslav; Hanzlíková, Iveta; Moulisová, Alena; Dušková, Šárka; Hejl, Kamil; Bednářová, Aneta; Dabrowská, Ludmila; Linhart, Igor

    2016-04-18

    A new experimental model was designed to study the fate of globin adducts with styrene 7,8-oxide (SO), a metabolic intermediate of styrene and a model electrophilic compound. Rat erythrocytes were incubated with SO at 7 or 22 °C. Levels of specific amino acid adducts in globin were determined by LC/MS analysis of the globin hydrolysate, and erythrocytes with known adduct content were administered intravenously to recipient rats. The course of adduct elimination from the rat blood was measured over the following 50 days. In the erythrocytes incubated at 22 °C, a rapid decline in the adduct levels on the first day post-transfusion followed by a slow phase of elimination was observed. In contrast, the adduct elimination in erythrocytes incubated at 7 °C was nearly linear, copying elimination of intact erythrocytes. In the urine of recipient rats, regioisomeric SO adducts at cysteine, valine, lysine, and histidine in the form of amino acid adducts and/or their acetylated metabolites as well as SO-dipeptide adducts were identified by LC/MS supported by synthesized reference standards. S-(2-Hydroxy-1-phenylethyl)cysteine and S-(2-hydroxy-2-phenylethyl)cysteine, the most abundant globin adducts, were excreted predominantly in the form of the corresponding urinary mercapturic acids (HPEMAs). Massive elimination of HPEMAs via urine occurred within the first day from the erythrocytes incubated at both 7 and 22 °C. However, erythrocytes incubated at 7 °C also showed a slow second phase of elimination such that HPEMAs were detected in urine up to 50 days post-transfusion. These results indicate for the first time that globin adducts can be cleaved in vivo to modified amino acids and dipeptides. The cleavage products and/or their predictable metabolites are excreted in urine over the whole life span of erythrocytes. Some of the urinary adducts may represent a new type of noninvasive biomarker for exposure to adduct-forming chemicals.

  17. Synthesis and Isolation of cis-2 Regiospecific Ethylene-Tethered Indene Dimer-[70]Fullerene Adduct for Polymer Solar Cell Applications.

    Science.gov (United States)

    Tao, Ran; Umeyama, Tomokazu; Higashino, Tomohiro; Koganezawa, Tomoyuki; Imahori, Hiroshi

    2015-08-05

    Although the utilization of [70]fullerene bis-adducts can enhance the power conversion efficiencies of polymer solar cells (PSCs) owing to their strong absorption intensities and high-lying lowest unoccupied molecular orbital energy levels, this synthetic strategy typically yields a mixture of regioisomers that would mask the intrinsic device performances depending on the substituent pattern on the [70]fullerene derivatives. In this study, a single cis-2 regioisomer of C70 bis-adduct (cis-2-[70]BIEC) has been prepared for the first time by the same strategy that had been applied to [60]fullerene to obtain a regioisomerically pure C60 bis-adduct (cis-2-[60]BIEC). Diels-Alder reaction was conducted between a rationally designed ethylene-tethered indene dimer and [70]fullerene, followed by isolation using high-performance liquid chromatography suitable for the separation of fullerene derivatives. A series of structural analysis techniques including NMR spectroscopies and X-ray crystallography were used to identify the absolute configuration of the bis-adduct. A systematic study on the optical, electrochemical, and photovoltaic properties of cis-2-[70]BIEC as well as the corresponding regioisomer mixture (bis-[70]BIEC) and the monoadduct (α-mono-[70]BIEC) has been performed to examine the effect of the pure cis-2 regioisomer. More importantly, their properties are compared with those of cis-2-[60]BIEC to address the effect of fullerene cage structures, that is, C60 versus C70. The PSC based on cis-2-[70]BIEC and poly(3-hexylthiophene) showed a remarkable power conversion efficiency of 4.2%, which is higher than those with bis-[70]BIEC (2.2%), α-mono-[70]BIEC (2.2%), cis-2-[60]BIEC (2.8%), and even a prevalent high-performance C70 monoadduct ([70]PCBM, 3.8%). Our synthetic strategy will pave the way for further development on the rational design and isolation of single fullerene bis-adduct regioisomers exhibiting high device performances.

  18. Chemical interactions in complex matrices: Determination of polar impurities in biofuels and fuel contaminants in building materials

    Science.gov (United States)

    Baglayeva, Ganna

    monoacylglycerols was developed. The identification and quantification of analytes were performed using a 15-m high temperature capillary column (DB-1HT) with a GC coupled to both flame ionization and mass spectrometric detectors. To eliminate discrimination of low or high molecular weight species, programmed temperature vaporization (PTV) injection parameters were optimized using design of experiments methodology. Evaluation of the column temperature program and MS parameters allowed achieving separation of majority of target compounds based on their total number of carbon atoms, regioisomerization and, to some extent, degree of unsaturation.

  19. Tetrachlorofluorescein TInsP as a Substrate Analog Probe for Measuring Phytase Activity in Surface Water: Proof of Concept.

    Science.gov (United States)

    Berry, Duane F; Harich, Kim

    2013-01-01

    An innovative approach for measuring phytase activity (PA) in surface water is presented. A substrate analog of -inositol hexakis(dihydrogen) phosphate (InsP), commonly referred to as phytic acid, 1--5--(1-oxo-1-(2' ,4,7,7' -tetrachloro-3',6'-dihydroxy-3-oxo-3H-spiro[isobenzofuran-1,9'-xanthen]-6-yl)-5,8,11-trioxa-2-azatridecan-13-yl)-inositol 1,2,3,4,6-pentakis--(dihydrogen) phosphate, referred to as tetrachlorofluorescein (TET) tethered (T)InsP, has been developed that can be used to monitor the (phytase-catalyzed) phosphate ester bond-cleavage reaction. Test phytases, (wheat [4-] and [3-] phytase) sequentially remove phosphate groups from TET TInsP, producing dephosphorylated probe species that were readily separated by reversed-phase high-performance liquid chromatography (RP-HPLC). Because dephosphorylated probe species retain the TET group, highly sensitive quantification could be achieved using fluorescence detection (excitation/emission ' = 245/540 nm). Calibration curves for TET TInsP, which could be used as a standard for quantifying all probe species, were linear ( > 0.999) over the range of concentrations tested. Phytase-generated dephosphorylated probe species were characterized or identified using RP-HPLC with mass spectrometry. Results of mass spectrometry analysis show that the RP-HPLC system was capable of distinguishing between dephosphorylated probe species at the regioisomeric level. The TET TInsP molecular probe was used to successfully measure PA in pond water. We found that the PA associated with the particulate plus water-soluble fraction was greater than that observed for the water-soluble fraction alone. Moreover, it appeared that 4- and 3-phytase were active in pond water based on an analysis of the chromatographic profile (i.e., elution sequence) of dephosphorylated probe species produced. The advent of a fluorescent substrate analog of InsP affords environmental scientists with the means to unambiguously quantify an extremely small

  20. Synthetic biology of proteins: tuning GFPs folding and stability with fluoroproline.

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    Thomas Steiner

    Full Text Available BACKGROUND: Proline residues affect protein folding and stability via cis/trans isomerization of peptide bonds and by the C(gamma-exo or -endo puckering of their pyrrolidine rings. Peptide bond conformation as well as puckering propensity can be manipulated by proper choice of ring substituents, e.g. C(gamma-fluorination. Synthetic chemistry has routinely exploited ring-substituted proline analogs in order to change, modulate or control folding and stability of peptides. METHODOLOGY/PRINCIPAL FINDINGS: In order to transmit this synthetic strategy to complex proteins, the ten proline residues of enhanced green fluorescent protein (EGFP were globally replaced by (4R- and (4S-fluoroprolines (FPro. By this approach, we expected to affect the cis/trans peptidyl-proline bond isomerization and pyrrolidine ring puckering, which are responsible for the slow folding of this protein. Expression of both protein variants occurred at levels comparable to the parent protein, but the (4R-FPro-EGFP resulted in irreversibly unfolded inclusion bodies, whereas the (4S-FPro-EGFP led to a soluble fluorescent protein. Upon thermal denaturation, refolding of this variant occurs at significantly higher rates than the parent EGFP. Comparative inspection of the X-ray structures of EGFP and (4S-FPro-EGFP allowed to correlate the significantly improved refolding with the C(gamma-endo puckering of the pyrrolidine rings, which is favored by 4S-fluorination, and to lesser extents with the cis/trans isomerization of the prolines. CONCLUSIONS/SIGNIFICANCE: We discovered that the folding rates and stability of GFP are affected to a lesser extent by cis/trans isomerization of the proline bonds than by the puckering of pyrrolidine rings. In the C(gamma-endo conformation the fluorine atoms are positioned in the structural context of the GFP such that a network of favorable local interactions is established. From these results the combined use of synthetic amino acids along with

  1. Co-crystals of 3-de­oxy-3-fluoro-α-d-glucopyran­ose and 3-de­oxy-3-fluoro-β-d-glucopyran­ose

    Science.gov (United States)

    Zhang, Wenhui; Oliver, Allen G.; Serianni, Anthony S.

    2010-01-01

    3-De­oxy-3-fluoro-d-glucopyran­ose crystallizes from acetone to give a unit cell containing two crystallographically independent mol­ecules. One of these mol­ecules (at site A) is structurally homogeneous and corresponds to 3-de­oxy-3-fluoro-β-d-glucopyran­ose, C6H11FO5, (I). The second mol­ecule (at site B) is structurally heterogeneous and corresponds to a mixture of (I) and 3-de­oxy-3-fluoro-α-d-glucopyran­ose, (II); treatment of the diffraction data using partial-occupancy oxygen at the anomeric center gave a high-quality packing model with an occupancy ratio of 0.84:0.16 for (II):(I) at site B. The mixture of α- and β-anomers at site B appears to be accommodated in the lattice because hydrogen-bonding partners are present to hydrogen bond to the anomeric OH group in either an axial or equatorial orientation. Cremer–Pople analysis of (I) and (II) shows the pyranosyl ring of (II) to be slightly more distorted than that of (I) [θ(I) = 3.85 (15)° and θ(II) = 6.35 (16)°], but the general direction of distortion is similar in both structures [ϕ(I) = 67 (2)° (B C1,C4) and ϕ(II) = 26.0 (15)° (C3 TB C1); B = boat conformation and TB = twist-boat conformation]. The exocyclic hy­droxy­methyl (–CH2OH) conformation is gg (gauche–gauche) (H5 anti to O6) in both (I) and (II). Structural comparisons of (I) and (II) to related unsubstituted, de­oxy and fluorine-substituted monosaccharides show that the gluco ring can assume a wide range of distorted chair structures in the crystalline state depending on ring substitution patterns. PMID:21051824

  2. Crystal Structure Studies on p-Substitutedbenzenesulphonamides 4-X-C6H4SO2NH2 (X = CH3, NH2 F, Cl or Br)

    Science.gov (United States)

    Thimme Gowda, B.; Jyothi, K.; Kožíšek, Jozef; Fuess, Hartmut

    2003-11-01

    Effect of ring substitution on the crystal structures of p-substitutedbenzenesulphonamides, p-XC6H4SO2NH2 (X = F, Cl, Br, CH3 or NH2) has been studied by determining the crystal structures of 4-chlorobenzenesulphonamide (4-ClC6H4SO2NH2) and 4-bromobenzenesulphonamide (4-BrC6H4SO2NH2) and analyzing the results along with the structures of 4-methylbenzenesulphonamide (4-CH3C6H4SO2NH2), 4-fluorobenzene-sulphonamide (4-FC6H4SO2NH2) and 4-aminobenzenesulphonamide (4-NH2C6H4SO2NH2). The crystal type, space group, formula units and lattice constants in Å of new structures are: (4-ClC6H4SO2NH2); monoclinic, P21/n, Z = 4, a = 6.6276(10), b = 16.219(3), c = 7.5716(10), β = 93.387(14)°; (4-BrC6H4SO2NH2): monoclinic, P 21/n, Z = 4, a = 6.5660(10), b = 16.4630(10), c = 7.6900(10), β = 92.760(10)°. Orientation of the amine group with respect to the phenyl ring is given by the torsion angles C(2)-C(1)-S-N: 70.9° and C(6)-C(1)-S-N: -108.5°. Similarly, the orientation of S, O(1) and O(2) with respect to the ring are given by torsion angles. The comparison of bond lengths and bond angles of 4-fluoro-, 4-chloro-, 4-bromo-, 4-methyl- and 4-amino-benzenesulphonamides reveal that the S-N and C-S bond lengths decrease with the introduction of electron-withdrawing substituents such as F, Cl or Br, while these groups do not have significant effects on the S-O distances. The effect on ring C-C distances was not uniform. Substitution of F, Cl or Br decreases the O-S-N bond angle, but increases the O-S-N, N-S-C(1) and C(3)-C(4)-C(5) bond angles.

  3. Hydrothermal Reactivity of Amines

    Science.gov (United States)

    Robinson, K.; Shock, E.; Hartnett, H. E.; Williams, L. B.; Gould, I.

    2013-12-01

    The reactivity of aqueous amines depends on temperature, pH, and redox state [1], all of which are highly variable in hydrothermal systems. Temperature and pH affect the ratio of protonated to unprotonated amines (R-NH2 + H+ = R-NH3+), which act as nucleophiles and electrophiles, respectively. We hypothesize that this dual nature can explain the pH dependence of reaction rates, and predict that rates will approach a maximum at pH = pKa where the ratio of protonated and unprotonated amines approaches one and the two compounds are poised to react with one another. Higher temperatures in hydrothermal systems allow for more rapid reaction rates, readily reversible reactions, and unique carbon-nitrogen chemistry in which water acts as a reagent in addition to being the solvent. In this study, aqueous benzylamine was used as a model compound to explore the reaction mechanisms, kinetics, and equilibria of amines under hydrothermal conditions. Experiments were carried out in anoxic silica glass tubes at 250°C (Psat) using phosphate-buffered solutions to observe changes in reaction rates and product distributions as a function of pH. The rate of decomposition of benzylamine was much faster at pH 4 than at pH 9, consistent with the prediction that benzylamine acts as both nucleophile and an electrophile, and our estimate that the pKa of benzylamine is ~5 at 250°C and Psat. Accordingly, dibenzylamine is the primary product of the reaction of two benzylamine molecules, and this reaction is readily reversible under hydrothermal conditions. Extremely acidic or basic pH can be used to suppress dibenzylamine production, which also suppresses the formation of all other major products, including toluene, benzyl alcohol, dibenzylimine, and tribenzylamine. This suggests that dibenzylamine is the lone primary product that then itself reacts as a precursor to produce the above compounds. Analog experiments performed with ring-substituted benzylamine derivatives and chiral

  4. Crystal structures of three substituted 3-aryl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-ones

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    Hemant P. Yennawar

    2016-08-01

    Full Text Available Three ring-substituted 3-aryl analogs of 2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one, namely 3-(4-methoxyphenyl-2-phenyl-4H-1,3-benzothiazin-4-one, C21H17NO2S, (I, 2-phenyl-3-[4-(trifluoromethylphenyl]-2,3-dihydro-4H-1,3-benzothiazin-4-one toluene hemisolvate, C21H14F3NOS·0.5C7H8, (II, and 3-(3-bromophenyl-2-phenyl-2,3-dihydro-4H-1,3-benzothiazin-4-one toluene hemisolvate, C20H14BrNOS·0.5C7H8, (III, were synthesized and their crystal structures determined. The hemisolvates differ in that in (II, the asymmetric unit comprises two molecules of the benzothiazinone compound and a toluene solvent molecule, whereas in (III, the unit comprises one benzothiazinone molecule and a half-occupancy toluene solvent molecule. All crystals are of racemic mixtures of the chiral 2-C atom of the thiazine moiety, which in all structures has a screw-boat puckering, with the puckering amplitude values within the range 0.575–0.603 Å. In all three structures, the benzene plane of the benzothiazine system makes a dihedral angle in the range 78.60 (5 to 98.40 (5° with the unsubstituted benzene plane and in the range 70.50 (1 to 121.00 (5° with the substituted benzene plane. The CF3 substituent group in one of the molecules of (II shows positional disorder, with an occupancy ratio of 0.57 (3:0.43 (3. In the crystals of (I and (II, weak intermolecular C—H...O interactions are present, giving in (I, molecules arranged in a plane parallel to (010, and in (II, chains along a. In addition, all three structures show weak C—H...π interactions involving various aromatic rings.

  5. Optimization of alkylating agent prodrugs derived from phenol and aniline mustards: a new clinical candidate prodrug (ZD2767) for antibody-directed enzyme prodrug therapy (ADEPT).

    Science.gov (United States)

    Springer, C J; Dowell, R; Burke, P J; Hadley, E; Davis, D H; Blakey, D C; Melton, R G; Niculescu-Duvaz, I

    1995-12-22

    Sixteen novel potential prodrugs derived from phenol or aniline mustards and their 16 corresponding drugs with ring substitution and/or different alkylating functionalities were designed. The [[[4-]bis(2-bromoethyl)-(1a), [[[4-[bis(2-iodoethyl)-(1b), and [[[4-[(2-chloroethyl)-[2-(mesyloxy)ethyl]amino]phenyl]oxy] carbonyl]-L-glutamic acids (1c), their [[[2- and 3-substituted-4-[bis(2-chloroethyl)amino]phenyl]oxy]carbonyl]-L- glutamic acids (1e-1), and the [[3-substituted-4-[bis(2-chloroethyl)amino]phenyl]carbamoyl]-L- glutamic acids (1o-r) were synthesized. They are bifunctional alkylating agents in which the activating effect of the phenolic hydroxyl or amino function is masked through an oxycarbonyl or a carbamoyl bond to a glutamic acid. These prodrugs were designed to be activated to their corresponding phenol and aniline nitrogen mustard drugs at a tumor site by prior administration of a monoclonal antibody conjugated to the bacterial enzyme carboxypeptidase G2 (CPG2) in antibody-directed enzyme prodrug therapy (ADEPT). The synthesis of the analogous novel parent drugs (2a-r) is also described. The viability of a colorectal cell line (LoVo) was monitored with the potential prodrugs and the parent drugs. The differential in the cytotoxicity between the potential prodrugs and their corresponding active drugs ranged between 12 and > 195 fold. Compounds 1b-d,f,o exhibited substantial prodrug activity, since a cytotoxicity differential of > 100 was achieved compared to 2b-d,f,o respectively. The ability of the potential prodrugs to act as substrates for CPG2 was determined (kinetic parameters KM and kcat), and the chemical stability was measured for all the compounds. The unsubstituted phenols with different alkylating functionalities (1a-c) proved to have the highest ratio of the substrates kcat:KM. From these studies [[[4-[bis(2-iodoethyl)amino]phenyl]oxy]carbonyl]-L-glutamic acid (1b) emerges as a new ADEPT clinical trial candidate due to its physicochemical and

  6. Multivalent benzene polyphosphate derivatives are non-Ca(2+)-mobilizing Ins(1,4,5)P3 receptor antagonists.

    Science.gov (United States)

    Mills, Stephen J; Luyten, Tomas; Erneux, Christophe; Parys, Jan B; Potter, Barry V L

    2012-12-01

    Inositol 1,4,5-trisphosphate [Ins(1,4,5)P31] mobilizes intracellular Ca(2+) through the Ins(1,4,5)P3 receptor [InsP3R]. Although some progress has been made in the design of synthetic InsP3R partial agonists and antagonists, there are still few examples of useful small molecule competitive antagonists. A "multivalent" approach is explored and new dimeric polyphosphorylated aromatic derivatives were designed, synthesized and biologically evaluated. The established weak InsP3R ligand benzene 1,2,4-trisphosphate [Bz(1,2,4)P32] is dimerized through its 5-position in two different ways, first directly as the biphenyl derivative biphenyl 2,2',4,4',5,5'-hexakisphosphate, [BiPh(2,2',4,4',5,5')P68] and with its regioisomeric biphenyl 3,3',4,4',5,5'-hexakisphosphate [BiPh(3,3',4,4',5,5')P611]. Secondly, a linker motif is introduced in a flexible ethylene-bridged dimer (9) with its corresponding 1,2-bisphosphate dimer (10), both loosely analogous to the very weak antagonist 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA 7). In permeabilized L15 fibroblasts overexpressing type 1 InsP3R, BiPh(2,2',4,4',5,5')P6 (8) inhibits Ins(1,4,5)P3-induced Ca(2+) release in a apparently competitive fashion [IC50 187 nM] and the Bz(1,2,4)P3 dimer (9) is only slightly weaker [IC50 380 nM]. Compounds were also evaluated against type I Ins(1,4,5)P3 5-phosphatase. All compounds are resistant to dephosphorylation, with BiPh(2,2',4,4',5,5')P6 (8), being the most effective inhibitor of any biphenyl derivative synthesized to date [IC50 480 nM] and the Bz(1,2,4)P3 ethylene dimer (9) weaker [IC50 3.55 μM]. BiPh(3,3',4,4',5,5')P6 (11) also inhibits 5-phosphatase [IC50 730 nM] and exhibits unexpected Ca(2+) releasing activity [EC50 800 nM]. Thus, relocation of only a single mirrored phenyl phosphate group in (11) from that of antagonist (8) does not markedly change enzyme inhibitory activity, but elicits a dramatic switch in Ca(2+)-releasing activity. Such new agents demonstrate the

  7. Low-dimensional coordination polymeric structures in alkali metal complex salts of the herbicide (2,4-dichlorophenoxy)acetic acid (2,4-D).

    Science.gov (United States)

    Smith, Graham

    2015-02-01

    The Li, Rb and Cs complexes with the herbicide (2,4-dichlorophenoxy)acetic acid (2,4-D), namely poly[[aqua[μ3-(2,4-dichlorophenoxy)acetato-κ(3)O(1):O(1):O(1')]lithium(I)] dihydrate], {[Li(C8H5Cl2O3)(H2O)]·2H2O}n, (I), poly[μ-aqua-bis[μ3-(2,4-dichlorophenoxy)acetato-κ(4)O(1):O(1'):O(1'),Cl(2)]dirubidium(I)], [Rb2(C8H5Cl2O3)2(H2O)]n, (II), and poly[μ-aqua-bis[μ3-(2,4-dichlorophenoxy)acetato-κ(5)O(1):O(1'):O(1'),O(2),Cl(2)]dicaesium(I)], [Cs2(C8H5Cl2O3)2(H2O)]n, (III), respectively, have been determined and their two-dimensional polymeric structures are described. In (I), the slightly distorted tetrahedral LiO4 coordination involves three carboxylate O-atom donors, of which two are bridging, and a monodentate aqua ligand, together with two water molecules of solvation. Conjoined six-membered ring systems generate a one-dimensional coordination polymeric chain which extends along b and interspecies water O-H...O hydrogen-bonding interactions give the overall two-dimensional layers which lie parallel to (001). In hemihydrate complex (II), the irregular octahedral RbO5Cl coordination about Rb(+) comprises a single bridging water molecule which lies on a twofold rotation axis, a bidentate O(carboxy),Cl-chelate interaction and three bridging carboxylate O-atom bonding interactions from the 2,4-D ligand. A two-dimensional coordination polymeric layer structure lying parallel to (100) is formed through a number of conjoined cyclic bridges, including a centrosymmetric four-membered Rb2O2 ring system with an Rb...Rb separation of 4.3312 (5) Å. The coordinated water molecule forms intralayer aqua-carboxylate O-H...O hydrogen bonds. Complex (III) comprises two crystallographically independent (Z' = 2) irregular CsO6Cl coordination centres, each comprising two O-atom donors (carboxylate and phenoxy) and a ring-substituted Cl-atom donor from the 2,4-D ligand species in a tridentate chelate mode, two O-atom donors from bridging carboxylate groups and one from a

  8. Mathematical models to correlate molecular topology with substrate affinity of the glycine antagonist in glutamate receptors Generación de modelos matemáticos correlacionales entre afinidad y descriptores topológicos moleculares de antagonistas de glicina en receptores de glutamato

    Directory of Open Access Journals (Sweden)

    Guillermo Narváez

    2010-08-01

    Full Text Available Introduction. Mathematical models that correlate chemical structure with biological activity have been useful in the design of new drugs and can be used to predict biological behavior of new, chemically related molecules.
    Objectives. A mathematical model was generated to correlate the substrate affinities with variations in the molecular topology of glycine antagonists in NMDA sub-class glutamate receptor and, subsequently, to propose new molecules with antagonist activity.
    Materials and methods. By use of molecular connectivity indexes, the electronic structure and atomic bonding patterns of 45 glycine antagonists were coded. Correlation between connectivity indexes and antagonist affinity was determined by regression analysis.
    Results. The connectivity index that best described affinity behavior was 4Xvpc, which indicates the relative importance of heteroatoms, the vicinity of aromatic ring substitutes, and valency gradient. The equations generated predicted new antagonist affinities, and the model was able to suggest structural requirements for designating compounds with increased affinity. Twelve new molecules were proposed, from which three appeared promising-based of the affinities previously calculated by means of the new equations. Energetic interaction analysis was developed as a control for the mathematical methodology.
    Conclusion. Glycine antagonists' structure were analyzed mathematically by means of connectivity indexes. The equations modeled receptor behavior and contributed useful information for new antagonist design.
    Introducción. Los modelos matemáticos que correlacionan la estructura química con la actividad biológica son útiles en el diseño de nuevos fármacos, y pueden emplearse para predecir el comportamiento biológico de moléculas nuevas químicamente relacionadas.
    Objetivos. Generar un modelo matemático que correlacione la afinidad y la topología molecular de antagonistas de

  9. Novel method for determining DDT in vapour and particulate phases within contaminated indoor air in a malaria area of South Africa

    Energy Technology Data Exchange (ETDEWEB)

    Naude, Yvette, E-mail: yvette.naude@up.ac.za [Department of Chemistry, University of Pretoria, Private Bag X20, Hatfield 0028, Pretoria (South Africa); Rohwer, Egmont R., E-mail: egmont.rohwer@up.ac.za [Department of Chemistry, University of Pretoria, Private Bag X20, Hatfield 0028, Pretoria (South Africa)

    2012-06-12

    isotopically labelled ring substituted {sup 13}C{sub 12} -p,p Prime -DDT as an internal standard. Limits of detection were 0.07-0.35 ng m{sup -3} for p,p Prime -DDT, o,p Prime -DDT, p,p Prime -DDD, o,p Prime -DDD, p,p Prime -DDE and o,p Prime -DDE. Ratios of airborne p,p Prime -DDD/p,p Prime -DDT and of o,p Prime -DDT/p,p Prime -DDT are unusual and do not match the ideal certified ingredient composition required of commercial DDT. Results suggest that the DDT products used for indoor residual spraying (IRS) prior to, and during 2007, may have been compromised with regards to insecticidal efficacy, demonstrating the power of this new environmental forensics tool.

  10. Hybrid Theranostic Platforms for Cancer Nanomedical Treatment

    KAUST Repository

    Julfakyan, Khachatur

    2015-10-01

    Cancer is a leading case of mortality worldwide. Governments spent multibillion expenses on treatment and palliative care of diseased people. Despite these generous funding and intensive research with aim to find a cure or efficient treatment for cancer, until now there is a lack in selective cancer management strategies. Conventional treatment strategies for cancer, such as surgery, cytotoxic chemotherapy, radiation therapy, hormone therapy don’t have selectivity toward cancer – the property of discrimination of healthy organs and tissues from the diseased site. Chemotherapy is very challenging as the difference between effective and lethal doses is very minuscule in most cases. Moreover, devastating side effects dramatically changes the quality of life for cancer patients. To address these issues two main strategies are intensively utilized in chemistry: (I) the design and synthesis of novel anticancer organic compounds with higher selectivity and low toxicity profiles and the second, design and preparation of biocompatible nanocarriers for imaging and anticancer compound selective delivery nanomedicine. The following dissertation combines the above two strategies as bellows: First project is related to the design and synthetic route development toward novel nature-inspired group of heterocyclic compounds – iso-Phidianidines. The second project focused on design, preparation and evaluation of hybrid theranostics (therapeutic and diagnostic in a single entity). Chapter 1 is a general background review of the major topics that will be discussed in this dissertation. The first efficient and high-yielding synthetic route toward iso-phidianidines, containing regioisomeric form of 1,2,4-oxadiazole linked to the indole via methylene bridge is reported in Chapter 2. In vitro test of the synthesized library of iso-phidianidines revealed micromolar range of cytotoxicity toward human cervical cancer cell line. Structure activity relationship revealed the importance of