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Sample records for antioxidant-conjugated difluorodiarylidenyl piperidones

  1. 3,5-Bis(3-alkylaminomethyl-4-hydroxybenzylidene)-4-piperidones: A Novel Class of Potent Tumor-Selective Cytotoxins.

    Science.gov (United States)

    Karki, Subhas S; Das, Umashankar; Umemura, Naoki; Sakagami, Hiroshi; Iwamoto, Shoko; Kawase, Masami; Balzarini, Jan; De Clercq, Erik; Dimmock, Stephen G; Dimmock, Jonathan R

    2016-01-28

    Novel 4-piperidone derivatives 2a-f are disclosed as potent cytotoxins. Many of these compounds are more potent than the reference drug melphalan. The compounds in series 2, 4-7 display selective toxicities toward various neoplasms compared to some normal cells. 2a is one of the promising lead molecules that display >11-fold higher growth inhibiting potency than 5-fluorouracil against human colon cancer cells. 2a induces apoptosis, DNA fragmentation, and cleavage of poly ADP-ribose polymerase.

  2. One-Pot Two-Step Organocatalytic Asymmetric Synthesis of Spirocyclic Piperidones via Wolff Rearrangement–Amidation–Michael–Hemiaminalization Sequence

    Directory of Open Access Journals (Sweden)

    Yanqing Liu

    2017-02-01

    Full Text Available A highly enantioselective organocatalytic Wolff rearrangement–amidation–Michael–hemiaminalization stepwise reaction is described involving a cyclic 2-diazo-1,3-diketone, primary amine and α,β-unsaturated aldehyde. Product stereocontrol can be achieved by adjusting the sequence of steps in this one-pot multicomponent reaction. This approach was used to synthesize various optically active spirocyclic piperidones with three stereogenic centers and multiple functional groups in good yields up to 76%, moderate diastereoselectivities of up to 80:20 and high enantioselectivities up to 97%.

  3. 1-[3-(2-Hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones: A novel cluster of P-glycoprotein dependent multidrug resistance modulators.

    Science.gov (United States)

    Das, Umashankar; Pati, Hari N; Baráth, Zoltan; Csonka, Ákos; Molnár, Joseph; Dimmock, Jonathan R

    2016-02-15

    A series of 1-[3-(2-hydroxyethylsulfanyl)propanoyl]-3,5-bis(benzylidene)-4-piperidones 4a-e display promising P-glycoprotein dependent multidrug resistance (MDR) revertant properties and are significantly more potent than a reference drug verapamil when evaluated against L-5178Y MDR lymphoma cells. These dienones may be referred to as dual agents having both MDR revertant properties and tumour-selective cytotoxicity. In particular, 3,5-bis(4-chlorobenzylidene)-1-[3-(2-hydroxyethylsulfanyl]propanoyl-4-piperidone 4d emerged as a lead molecule for further development based on its MDR revertant properties, cytotoxic potencies and tumour-selective toxicity. The structure-activity relationships reveal important structural requirements for further designing of potent MDR revertants.

  4. Investigation of the role of stereoelectronic effects in the conformation of piperidones by NMR spectroscopy and X-ray diffraction

    Directory of Open Access Journals (Sweden)

    Cesar Garcias-Morales

    2015-10-01

    Full Text Available This paper reports the synthesis of a series of piperidones 1–8 by the Mannich reaction and analysis of their structures and conformations in solution by NMR and mass spectrometry. The six-membered rings in 2,4,6,8-tetraphenyl-3,7-diazabicyclo[3.3.1]nonan-9-ones, compounds 1 and 2, adopt a chair–boat conformation, while those in 2,4-diphenyl-3-azabicyclo[3.3.1]nonan-9-ones, compounds 3–8, adopt a chair–chair conformation because of stereoelectronic effects. These stereoelectronic effects were analyzed by the 1JC–H coupling constants, which were measured in the 13C satellites of the 1H NMR spectra obtained with the hetero-dqf pulse sequence. In the solid state, these stereoelectronic effects were investigated by measurement of X-ray diffraction data, the molecular geometry (torsional bond angles and bond distances, and inter- and intramolecular interactions, and by natural bond orbital analysis, which was performed using density functional theory at the ωB97XD/6311++G(d,p level. We found that one of the main factors influencing the conformational stability of 3–8 is the interaction between the lone-pair electrons of nitrogen and the antibonding sigma orbital of C(7–Heq (nN→σ*C–H(7eq, a type of hyperconjugative interaction.

  5. Highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid: Synthesis, characterization and theoretical investigations on the regiochemistry

    Science.gov (United States)

    Suresh Kumar, Raju; Almansour, Abdulrahman I.; Arumugam, Natarajan; Soliman, Saied M.; Ranjith Kumar, Raju; Ghabbour, Hazem A.

    2016-10-01

    The synthesis of highly functionalized dispiro oxindole-pyrrolo[1,2-c]thiazole-piperidone hybrid has been achieved regioselectively employing microwave-assisted three-component 1,3-dipolar cycloaddition. Structural elucidation of the compound has been accomplished using NMR spectroscopy and further confirmed by single crystal X-ray crystallographic studies. The molecular structure of the compound crystallized in monoclinic, P21/c, a = 11.6182 (2) Å, b = 12.2466 (2) Å, c = 21.7061 (3) Å, β = 103.018 (1)°, V = 3009.04 (8) Å3, Z = 4. The cycloaddition was found to proceed by normal electronic demand (NED) character with a significant high charge transfer (0.1247 eV) from the 1,3-dipole to the dipolarophile. The regiochemistry has been explained using the local reactivity descriptors obtained from the DFT calculations. The DFT optimized molecular structure agreed well with the X-ray results.

  6. 3,5-Bis(benzylidene)-1-[4-2-(morpholin-4-yl)ethoxyphenylcarbonyl]-4-piperidone hydrochloride: a lead tumor-specific cytotoxin which induces apoptosis and autophagy.

    Science.gov (United States)

    Das, Umashankar; Sakagami, Hiroshi; Chu, Qing; Wang, Qintao; Kawase, Masami; Selvakumar, Ponniah; Sharma, Rajendra K; Dimmock, Jonathan R

    2010-02-01

    A number of N-4-(2-aminoethoxy)phenylcarbonyl derivatives of various 3,5-bis(benzylidene)-4-piperidones 2-5 demonstrated noteworthy cytotoxic potencies towards human HL-60 leukemic cells as well as human HSC-2 and HSC-4 squamous cell carcinomas. In general, toxicity towards HGF, HPC, and HPLF normal cells was substantially lower. The highest selective toxicity was noted when the terminal base is morpholine. Lead optimization was based on finding compounds which had (i) high cytotoxic potencies, (ii) a greater toxicity to neoplasms than normal cells, and (iii) drug-likeness based on the rule of five. From the biodata generated, 5a evolved as a promising lead compound for further development. The mode of action of 5a included the induction of apoptosis in HL-60 cells in which internucleosomal DNA fragmentation and activation of caspase-3 was noted. In addition, 5a caused autophagy in HSC-2 cells.

  7. N-取代-3,5-二芳亚甲基-4-哌啶酮衍生物的合成与表征%Synthesis and characterization of N-substituted-3, 5-bis (arylidene)-4-piperidone derivatives

    Institute of Scientific and Technical Information of China (English)

    孙居锋; 李珂珂; 于晨; 代现平

    2011-01-01

    In order to research a kind of high potency, low tox-icity potential antitumour leading compounds,a few N-substi-tuted-3,5-bis(arylidene)-4-piperidones were synthesized taking N-substituted-4-piperidones and formaldehyde derivatives as starting materials with alcoholic NaOH or dry hydrogen chloride as catalyst by aldol condensation reaction inspected by TLC on the condition of 10 ℃ or 20 ℃ ,7 ~ 8 h,followed by recrystalization. The yield is over 49%. The structures were characterized by1 HNMR, X-ray crystallography with melting points. It was a convenient and efficient method in high yield. The compounds are used for antitumour evaluation in our next work.%为了研究一类高效低毒对耐药肿瘤有效的新型抗肿瘤先导化合物,以N-取代-4-哌啶酮和芳甲醛衍生物为原料,分别以氢氧化钠的乙醇溶液或干燥的氯化氢气体作催化剂,在10或20℃经过7~8h的羟醛缩合反应,TLC监测反应进程,最后经重结晶合成了3种标题化合物,收率达49%以上,并采用1HNMR、X-射线单晶衍射结合熔点对其结构进行了表征.该合成路线反应条件温和、操作简便,所得衍生物可用于下一步实验中抗肿瘤活性评价.

  8. N-(4-甲基苄基)-3,5-双(4-氯苄叉基)-4-哌啶酮的合成、单晶结构分析以及生物活性的测定%Synthesis, crystal structure and bioactivity of n -( 4 - methylbenzyl ) - 3,5 - bis ( 4 - chlorobenzylide ne ) -4 - piperidone

    Institute of Scientific and Technical Information of China (English)

    梁宇; 薛思佳

    2012-01-01

    A novel compound N - (4 - methylbenzyl) - 3,5 - bis ( 4 - chlorobenzylidene ) - 4 - piperidone was synthesized with 4 - methylbenzylamine as raw materials via a series of Michael addition,Dieckmann condensation,hydrolysis decarboxylation and Aldol condensation.The structure wasconfirmed by elemental analysis,1H NMR,IR,ESI and single -crystal X -ray diffraction.The crystal belongs to the monoclinic system,with space group P2 (1) corresponding to a =17.1226 (16),b=6.28396(6),c=21.468(2),α=90°,β3=99.753°,γ=90°,V=2276.5(4)3,Z=4,Dc =1.308 g/cm3 =0.304 mm-1,Mr =448.36,F(000) =936,S =1.019,the final R =0.0585 and wR =0.1456.The molecule was nonplanar,and the piperidine ring exhibited a sofa conformation.The carbon-carbon double bonds in the compound were both E-configuration.Neither intra- nor intermolecular hydrogen bonds was identified in the crystal structure.Assay-based antiproliferative activity study using leukemic cell lines K562 revealed that the compound had high effectiveness in inhibiting leukemia K562 cells proliferation.%以取代苄胺为原料,经过Michael加成、Dieckmann缩合、水解脱羧、羟醛缩合等反应,合成一个未见文献报道的化合物:N-(4-甲基苄基)-3,5-双(4-氯苄叉基)-4-哌啶酮.目标化合物的结构经元素分析、核磁共振氢谱(1H NMR)、红外光谱(IR)、质谱(EI- MS)及单晶X-射线衍射测定确定.该单晶属于单斜晶系,空间群为P2(1),a=17.1226(16),b =6.28396(6),c =21.468(2),α=90°,β=99.753°,γ =90°,V=2276.5(4) 3,Z=4,Dc=1.308g/cm3=0.304 mm-1,Mr =448.36,F(000) =936,S=1.019,R=0.0585以及wR =0.1456.目标化合物的结构是非平面的,哌啶环呈沙发构象.化合物中的碳碳双键都是E式构的.在晶体结构中没有分子内和分子间氢键存在.生物活性测试结果表明:目标化合物对白血病K562细胞系的增殖有明显的抑制作用,具有潜在的抗癌活性.

  9. Effect of piperidones on hydrogen permeation and corrosion inhibition of mild steel in acidic solutions

    Indian Academy of Sciences (India)

    S Muralidharan; R Chandrasekar; S V K Iyer

    2000-04-01

    The influence of 3-methyl-2,6-diphenyl piperidin-4-one (MDPO) and 2-phenyl decahydroquinoline-4-one (PDQO) synthesised in the laboratory on hydrogen permeation and corrosion inhibition of mild steel in 1N H2SO4 has been studied using weight loss and various electrochemical AC and DC corrosion-monitoring techniques. Both the compounds inhibit the corrosion of mild steel in H2SO4 Potentiodynamic polarisation studies clearly reveal that they behave predominantly as cathodic inhibitors. The extent of decrease in hydrogen permeation current through steel surfaces has been studied by the hydrogen electropermeation technique. Double layer capacitance () and charge transfer resistance () values are derived from Nyquist plots obtained from AC impedance studies. The adsorption of these compounds on mild steel surfaces from H2SO4 obeys Temkin’s adsorption isotherm.

  10. Solid phase total synthesis of the 3-amino-6-hydroxy-2-piperidone (Ahp) cyclodepsipeptide and protease inhibitor Symplocamide A.

    Science.gov (United States)

    Stolze, Sara C; Meltzer, Michael; Ehrmann, Michael; Kaiser, Markus

    2010-12-14

    The solid phase total synthesis of the marine cyanobacterial Ahp-cyclodepsipeptide Symplocamide A is reported as a model for a general route for the synthesis of tailor-made non-covalent serine protease inhibitors.

  11. A twist on facial selectivity of hydride reductions of cyclic ketones: twist-boat conformers in cyclohexanone, piperidone, and tropinone reactions.

    Science.gov (United States)

    Neufeldt, Sharon R; Jiménez-Osés, Gonzalo; Comins, Daniel L; Houk, K N

    2014-12-05

    The role of twist-boat conformers of cyclohexanones in hydride reductions was explored. The hydride reductions of a cis-2,6-disubstituted N-acylpiperidone, an N-acyltropinone, and tert-butylcyclohexanone by lithium aluminum hydride and by a bulky borohydride reagent were investigated computationally and compared to experiment. Our results indicate that in certain cases, factors such as substrate conformation, nucleophile bulkiness, and remote steric features can affect stereoselectivity in ways that are difficult to predict by the general Felkin-Anh model. In particular, we have calculated that a twist-boat conformation is relevant to the reactivity and facial selectivity of hydride reduction of cis-2,6-disubstituted N-acylpiperidones with a small hydride reagent (LiAlH4) but not with a bulky hydride (lithium triisopropylborohydride).

  12. Hemorrhage-induced interleukin-1 receptor pathway in lung is suppressed by 3,5-bis(2-fluorobenzylidene)-4-piperidone in a rat model of hypovolemic shock.

    Science.gov (United States)

    Yadav, Vivek R; Vilekar, Prachi; Awasthi, Shanjana; Awasthi, Vibhudutta

    2014-08-01

    Severe blood loss in victims of trauma creates an exaggerated inflammatory background that contributes to the development of intravascular coagulopathy and multiple organ dysfunction syndrome. We hypothesized that treatment with diphenyldifluoroketone EF24, an inhibitor of nuclear factor kappa-B, would have salutary effects in hemorrhagic shock. The objective of this study was to investigate the effect of EF24 on the expression of the interleukin-1 receptor (IL-1R) superfamily in a rat model of hypovolemic shock. Hypovolemia was induced by gradually withdrawing approximately 50% of circulating blood, and EF24 was administered intraperitoneally (0.2 mg/kg) in 50 μL of saline. After 6 h of shock, lung tissue was probed immunohistochemically and by immunoblotting to study the expression of Toll-like receptor 4 (TLR4), IL-1R, suppression of tumorigenicity 2 (ST2), and single immunoglobulin IL-1R-related (SIGIRR). The tissue-associated pro-inflammatory cytokines, tumor necrosis factor alpha (TNF-α) and IL-6, were measured by enzyme-linked immunosorbent assay. We observed a reduction in immunoreactive TLR4 and IL-1R1 in lung tissue of rats treated with EF24. Simultaneously, the pulmonary expression of ST2 and SIGIRR (the putative down-regulators of the pro-inflammatory IL-1R pathway) was increased in EF24-treated hemorrhaged rats. The concentration of hemorrhage-induced TNF-α and IL-6 in lung tissue homogenates was also reduced by EF24 treatment. These results confirm our previous in vitro observations in lipopolysaccharide-stimulated dendritic cells that EF24 beneficially modulates the IL-1R pathway and suggest that it could be investigated as an adjunct therapeutic in managing inflammation associated with hemorrhagic shock.

  13. Synthesis of 4-substituted tetrahydropyridines by cross-coupling of enol phosphates

    DEFF Research Database (Denmark)

    Larsen, U.S.; Martiny, L.; Begtrup, M.

    2005-01-01

    Enol phosphates, synthesized from 4-piperidone, react by palladium catalyzed cross-coupling with arylboronic acids and by iron and palladium catalyzed cross-coupling with Grignard reagents to give 4-substituted tetrahydropyridines. (c) 2005 Elsevier Ltd. All rights reserved.......Enol phosphates, synthesized from 4-piperidone, react by palladium catalyzed cross-coupling with arylboronic acids and by iron and palladium catalyzed cross-coupling with Grignard reagents to give 4-substituted tetrahydropyridines. (c) 2005 Elsevier Ltd. All rights reserved....

  14. 6-Membered ring intermediates in polymerization of N-carboxyanhydride-L-α-arginine in H2O

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    In polymerization of N-carboxyanhydride-L-α-arginine(L-Arg-NCA) in H2O,nucleophilic reaction of guanidine group with the carbonyl group of L-Arg-NCA leads to quick intramolecular rearrangement,yielding a 6-membered ring intermediate 1-amidino-3-amino-2-piperidone,which is either elongated by another L-Arg-NCA yielding arginyl-1-amidino-3-amino-2-piperidone or hydrolyzed to L-α-arginine.The oligoarginines are formed mainly through hydrolysis of arginyl-1-amidino-3-amino-2-piperidones.This is a unique pathway in polymerization of L-Arg-NCA with regard to the usual pathway of elongations by reaction of N-carboxyanhydride-L-α-amino acid with L-α-amino acid or oligopeptides.

  15. 6-Membered ring intermediates in polymerization of N-carboxyanhydride-L-a-arginine in H2O

    Institute of Scientific and Technical Information of China (English)

    XIN Liang; REN Jie; XIANG JunFeng; YAN Qin; XIE Yi; WANG KongJiang; LAI PingAn; BAI YaDuo

    2009-01-01

    In polymerization of N-carboxyanhydride-L-α-arginine (L-Arg-NCA) in H2O,nucleophilic reaction of guanidine group with the carbonyl group of L-Arg-NCA leads to quick intramolecular rearrangement,yielding a 6-membered ring intermediate 1-amidino-3-amino-2-piperidone,which is either elongated by another L-Arg-NCA yielding arginyl-1-amidino-3-amino-2-piperidone or hydrolyzed to L-α-arginine.The oligoarginines are formed mainly through hydrolysis of arginyl-1-amidino-3-amino-2-piperidones.This is a unique pathway in polymerization of L-Arg-NCA with regard to the usual pathway of elongations by reaction of N-carboxyanhydride-L-a-amino acid with L-a-amino acid or oligopeptides.

  16. A general A{sup 3}: coupling reaction based on functionalized alkynes

    Energy Technology Data Exchange (ETDEWEB)

    Wendler, Edison P.; Santos, Alcindo A. dos, E-mail: alcindo@iq.usp.br [Universidade de Sao Paulo (IQ/USP), SP (Brazil). Inst. de Quimica

    2013-10-01

    A range of hydroxypropargylpiperidones were efficiently obtained by a one-pot three-component coupling reaction of aldehydes, alkynols, and a primary amine equivalent (4-piperidone hydrochloride hydrate) in ethyl acetate using copper(I) chloride as a catalyst. The developed protocol proved to be equally efficient using a range of aliphatic aldehydes, including paraformaldehyde, and using protected and unprotected alkynols. (author)

  17. tert-Butyl 3-[N-(tert-butoxycarbonylmethylamino]-4-methoxyimino-3-methylpiperidine-1-carboxylate

    Directory of Open Access Journals (Sweden)

    Huiyuan Guo

    2009-02-01

    Full Text Available The title compound, C18H33N3O5, was prepared from N-tert-butoxycarbonyl-4-piperidone using a nine-step reaction, including condensation, methylation, oximation, hydrolysis, esterification, ammonolysis, Hoffmann degradation, tert-butoxycarbonyl protection and methylation. The E configuration of the methyloxime geometry of the compound is confirmed.

  18. A thermodynamic study of ketoreductase-catalyzed reactions 5. Reduction of substituted ketones in n-hexane

    Energy Technology Data Exchange (ETDEWEB)

    Tewari, Yadu B. [Biochemical Science and Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States)], E-mail: yadu.tewari@nist.gov; Vanderah, David J. [Biochemical Science and Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States)], E-mail: david.vanderah@nist.gov; Schantz, Michele M. [Biochemical Science and Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States)], E-mail: michele.schantz@nist.gov; Goldberg, Robert N. [Biochemical Science and Analytical Chemistry Division, National Institute of Standards and Technology, Gaithersburg, MD 20899 (United States)], E-mail: robert.goldberg@nist.gov; Rozzell, J. David [Codexis, Inc., 129 N. Hill Avenue, Pasadena, CA 91106 (United States)], E-mail: david.rozzell@codexis.com; Liebman, Joel F. [Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250 (United States)], E-mail: jliebman@umbc.edu; Hui, Raymond Wai-Man; Nissenbaum, Yitzy; Parniani, Ahmad Reza [Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, MD 21250 (United States)

    2008-04-15

    The equilibrium constants K for the ketoreductase-catalyzed reduction reactions of 1-benzyl-3-pyrrolidinone, ethyl 2-oxo-4-phenylbutyrate, ethyl 4-chloroacetoacetate, 1-benzyl-4-piperidone, and 1-benzyl-3-piperidone were measured in n-hexane at T = 298.15 K by using gas chromatography. The equilibrium constants for the reaction involving 1-benzyl-4-piperidone were also measured as a function of temperature (288.15 to 308.05) K. The calculated thermodynamic quantities for the reaction (1-benzyl-4-piperidone + 2-propanol = 1-benzyl-4-hydroxypiperidine + acetone) reaction carried out in n-hexane at T = 298.15 K are: K = (26.2 {+-} 1.7); {delta}{sub r}G{sub m}{sup 0}=-(8.10{+-}0.16)kJ.mol{sup -1}; {delta}{sub r}H{sub m}{sup 0}=-(3.44{+-}0.42)kJ.mol{sup -1}; and {delta}{sub r}S{sub m}{sup 0}=(15.6{+-}1.4)J.K{sup -1}.mol{sup -1}. The chirality of the hydroxyl products of the reactions has also been investigated. The results showed that the stereoselectivity of the hydroxyl products formed can be controlled by the selection of the solvent and enzyme used in these reactions. The thermochemical results for these reactions are compared with the results for reactions that have analogous structural features as well as with the results of quantum chemical calculations.

  19. Combinatorial Chemistry of Piperidine Based Carbohydrate Mimics

    DEFF Research Database (Denmark)

    Byrgesen, Elisabeth Vang; Nielsen, John; Willart, Marianne

    1997-01-01

    Piperidine carboxylic acids and 4-hydroxypiperidine-3-carboxylic acid, the latter obtained from bakers yeast reduction of the corresponding piperidone, were coupled in solid-phase synthesis to form simplified oligosaccharide analogues. A split-and-mix synthesis approach was used to create small c...

  20. 3,3,5,5-Tetramethyl-r-2,c-6-diphenylpiperidin-4-one

    Directory of Open Access Journals (Sweden)

    C. Govindaraju

    2012-07-01

    Full Text Available The piperidone ring of the title compound, C21H25NO, adopts a chair conformation with the two phenyl groups equatorially oriented and cis to each other. In the crystal, molecules are linked by weak N—H...O hydrogen bonds, forming chains parallel to [100].

  1. Fentanyl Synthetic Methodology: A Comparative Study

    Science.gov (United States)

    1992-03-01

    aluminum hydride (LiAIH 4 ) reduction of the intermediate Schiff base , 3, in ether gave compound 4. Subsequent acylation with propionyl anhydride in toluene... Schiff base , 13 gave a 65% of the product. Method D. 15 This method utilizes the commercially available 1-benzoyl-4-piperidone (15) (1 g/$15.00, Aldrich...as the starting material and the catalytic hydrogenation to reduce the Schiff base , 16. Acid hydrolysis of 17, followed by alkylation, gives fentanyl

  2. Synthesis of a family of spirocyclic scaffolds: building blocks for the exploration of chemical space.

    Science.gov (United States)

    Kumar, Sarvesh; Thornton, Paul D; Painter, Thomas O; Jain, Prashi; Downard, Jared; Douglas, Justin T; Santini, Conrad

    2013-07-05

    This report describes the preparation of a series of 17 novel racemic spirocyclic scaffolds that are intended for the creation of compound libraries by parallel synthesis for biological screening. Each scaffold features two points of orthogonal diversification. The scaffolds are related to each other in four ways: (1) through stepwise changes in the size of the nitrogen-bearing ring; (2) through the oxidation state of the carbon-centered point of diversification; (3) through the relative stereochemical orientation of the two diversification sites in those members that are stereogenic; and (4) through the provision of both saturated and unsaturated versions of the furan ring in the scaffold series derived from 3-piperidone. The scaffolds provide incremental changes in the relative orientation of the diversity components that would be introduced onto them. The scaffolds feature high sp(3) carbon content which is essential for the three-dimensional exploration of chemical space. This characteristic is particularly evident in those members of this family that bear two stereocenters, i.e., the two series derived from 3-piperidone and 3-pyrrolidinone. In the series derived from 3-piperidone we were able to "split the difference" between the two diastereomers by preparation of their corresponding unsaturated version.

  3. Asymmetric synthesis of (-)-adaline.

    Science.gov (United States)

    Itoh, Toshimasa; Yamazaki, Naoki; Kibayashi, Chihiro

    2002-07-25

    [reaction: see text] An enantioselective total synthesis of (-)-adaline has been achieved starting from a chiral 6,6-disubstituted piperidone derivative previously prepared by diastereoselective allylation of a chiral tricyclic N-acyl-N,O-acetal. The key steps include lithium ion-activated SN2-type alkynylation of the tricyclic N,O-acetal leading to exclusive formation of the (6S)-ethynylpiperidine and ring-closing olefin metathesis of the (2R,6S)-cis-2,6-dialkenylpiperidine for constructing the bridged azabicyclononane.

  4. Synthesis of novel precursors of Pfitzinger reaction: A facile one-pot strategy to the synthesis of quinoline carboxylic acid derivatives of pyrazolo-carbazoles and azacarbazoles

    Indian Academy of Sciences (India)

    Ruchi Tyagi; Bhawani Singh; D Kishore

    2012-03-01

    Interaction of 5-indazolyldiazonium chloride 2 with 2-hydroxymethylidene cyclohexanone 5 and -benzyl-3-hydroxymethylidene-4-piperidone 6 under the conditions of Japp-Klingemann reaction, followed by Fischer-indolization of the resulting hydrazones, formed the 5,7,8,9-tetrahydropyrazolo[4,3-b]carbazol- 6(1)-one 9 and 9-benzyl-5,7,8,9-tetrahydropyrido[2',3':4,5]pyrrolo[2,3-f]indazol-6(1)-one 10, respectively. Pfitzinger reaction of 9 and 10 with isatin in alkali afforded the corresponding quinoline carboxylic acid derivatives 12 and 13, respectively.

  5. Synthesis, structure, antitumor activity of novel pharmaceutical co-crystals based on bispyridyl-substituted α, β-unsaturated ketones with gallic acid

    Science.gov (United States)

    Liu, Lian-Dong; Liu, Shu-Lian; Liu, Zhi-Xian; Hou, Gui-Ge

    2016-05-01

    Three novel pharmaceutical co-crystals, (A)·(gallic acid) (1), (B)·(gallic acid) (2), and (C)·(gallic acid) (3) were generated based on 2,6-bis((pyridin-4-yl)methylene)cyclohexanone (A), N-methyl-3,5-bis((pyridin-3-yl)methylene)-4-piperidone (B), N-methyl-3,5-bis((pyridin-4-yl)methylene)-4-piperidone (C) with gallic acid, respectively. They are characterized by elemental analysis, FTIR spectroscopy, 1H NMR and single-crystal X-ray diffraction. Structural analysis reveals that two pharmaceutical ingredients link each other into H-bonding-driven 3D network in 1, 2, or 2D plane in 3. In addition, their antitumor activities against human neoplastic cell lines A549, SGC-7901, MCF-7, OVCA-433, HePG2 and cytotoxicity for HUVEC cell lines by CCK-8 method were evaluated primarily. Compared with gallic acid and free A, B and C, their antitumor activities have improved distinctly, while cytotoxicities have reduced markedly, especially for co-crystal 1. This is mainly because of the synergistic effect between pharmaceutical ingredients A, B, and C and gallic acid.

  6. Synthesis and analysis of the opioid analgesic [[sup 14]C]-fentanyl

    Energy Technology Data Exchange (ETDEWEB)

    Bagley, J.R.; Wilhelm, J.A. (Anaquest Inc., Murray Hill, NJ (United States))

    1992-11-01

    The synthesis of [[sup 14]C]-fentanyl, the radiolabelled congener of the potent opioid analgesic chosen for utilization in drug disposition studies, is described. [[sup 14]C]-Labelling was achieved in the first of two steps, a room temperature reduction of the in situ generated Schiff base from 1-phenylethyl-4-piperidone and [UL-[sup 14]C]-aniline hydrochloride with sodium triacetoxyborohydride. A nearly instantaneous production of fentanyl was accomplished at room temperature with the addition of propionyl chloride. The overall radiochemical yield was 18%. The method described is efficiently adaptable for submicromolar scale while yielding a product of sufficient specific activity for in vivo studies. Our solvent system for thin layer chromatography was superior to the USP system reported for chromatographic analysis of fentanyl. This is the first reported preparation of [[sup 14]C]-fentanyl with the radiolabel in the aniline benzene ring. (author).

  7. Stigonemapeptin, an Ahp-containing depsipeptide with elastase inhibitory activity from the bloom-forming freshwater cyanobacterium Stigonema sp.

    Science.gov (United States)

    Kang, Hahk-Soo; Krunic, Aleksej; Orjala, Jimmy

    2012-04-27

    Stigonemapeptin (1), a depsipeptide containing an Ahp (3-amino-6-hydroxy-2-piperidone) residue, was isolated from a bloom sample of the freshwater cyanobacterium Stigonema sp. collected from North Nokomis Lake in the Highland Lake District of northern Wisconsin. The planar structure was determined by 1D and 2D NMR experiments as well as HRESIMS analysis. The absolute configurations of the amino acids were determined using the advanced Marfey's method after acid hydrolysis. Stigonemapeptin (1), characterized by the presence of the Ahp residue, also contained the modified amino acids Abu (2-amino-2-butenoic acid) and N-formylated Pro. Stigonemapeptin (1) showed in vitro elastase and chymotrypsin inhibitory activity, with IC(50) values of 0.26 and 2.93 μM, respectively.

  8. 2,4-Bis(2-ethoxyphenyl-7-methyl-3-azabicyclo[3.3.1]nonan-9-one

    Directory of Open Access Journals (Sweden)

    P. Parthiban

    2011-06-01

    Full Text Available The crystal structure of the title compound, C25H31NO3, exists in a twin-chair conformation with an equatorial orientation of the ortho-ethoxyphenyl groups. According to Cremer and Pople [Cremer & Pople (1975, J. Am. Chem. Soc. 97, 1354–1358], both the piperidone and cyclohexanone rings are significantly puckered with total puckering amplitutdes QT of 0.5889 (18 and 0.554 (2 Å, respectively. The ortho-ethoxyphenyl groups are located on either side of the secondary amino group and make a dihedral angle of 12.41 (4° with respect to each other. The methyl group on the cyclohexanone part occupies an exocyclic equatorial disposition. The crystal packing is stabilized by weak van der Waals interactions.

  9. Synthesis of 5-oxyquinoline derivatives for reversal of multidrug resistance

    Directory of Open Access Journals (Sweden)

    Torsten Dittrich

    2012-10-01

    Full Text Available The inhibition of ABC (ATP binding cassette transporters is considered a powerful tool to reverse multidrug resistance. Zosuquidar featuring a difluorocyclopropyl-annulated dibenzosuberyl moiety has been found to be an inhibitor of the P-glycoprotein, one of the best-studied multidrug efflux pumps. Twelve 5-oxyisoquinoline derivatives, which are analogues of zosuquidar wherein the dibenzosuberyl-piperazine moiety is replaced by either a diarylaminopiperidine or a piperidone-derived acetal or thioacetal group, have been synthesized as pure enantiomers. Their inhibitory power has been evaluated for the bacterial multidrug-resistance ABC transporter LmrCD and fungal Pdr5. Four of the newly synthesized compounds reduced the transport activity to a higher degree than zosuquidar, being up to fourfold more efficient than the lead compound in the case of LmrCD and about two times better for Pdr5.

  10. The interpretation of the mass spectrum of an ornithine-containing lipid from Thiobacillus thiooxidans.

    Science.gov (United States)

    Hilker, D R; Gross, M L; Knocke, H W; Shively, J M

    1978-01-01

    The electron impact mass spectrum of a previously identified ornithine-containing lipid from Thiobacillus thiooxidans has been interpreted using exact mass measurements, low and high energy ionization, and defocused metastable studies. The spectrum, which did not contain a molecular ion for the intact lipid, was consistent with cyclization of the ornithine zwitterionic moiety with elimination of water to give 3[3'-(11,12-methylene-2-hydroxyoctadecanoxy)hexadecanylamine]-2-piperidone. Production of this sufficiently volatile species for mass spectral analysis was accomplished by gentle pyrolysis in the mass spectrometer source. The spectrum can be understood to arise by three primary decompositions which serve to separate the two fatty acid constituents. The remainder of the spectrum is consistent with the expected fragmentations of these constituents.

  11. The role of weak intermolecular C-H…F interactions in supramolecular assembly: Structural investigations on 3,5- dibenzylidene-piperidin-4-one and database analysis

    Indian Academy of Sciences (India)

    R S Rathore; N S Karthikeyan; Y Alekhya; K Sathiyanarayanan; P G Aravindan

    2011-07-01

    The fluorinated and non-fluorinated dibenzylidene-4-piperidones were synthesized and their structures examined using X-ray crystallography. Interestingly, the para-fluorosubstituted dibenzylidene compound, in contrast to other analogs, is characterized by C-H…F bonded one-dimensional packing motif. To evaluate the ability of hydrogen bond donors and acceptors for forming interactions, in general and competitive situation, we have defined statistical descriptors. Analysis of Cambridge Structural Database using these newly defined parameters reveals high propensity of C-H…F interactions in organic crystals. The present structural study suggests much larger role of fluorine driven intermolecular interactions that are even though weak, but possess significant ability to direct and alter the packing.

  12. Experimental and ab initio studies of the novel piperidine-containing acetylene glycols

    CERN Document Server

    Mirsakiyeva, Amina; Elgammal, Karim; Ten, Assel; Hugosson, Håkan W; Delin, Anna; Yu, Valentina K

    2015-01-01

    Synthesis routes of novel piperidine-containing diacetylene are presented. The new molecules are expected to exhibit plant growth stimulation properties. In particular, the yield in a situation of drought is expected to increase. The synthesis makes use of the Favorskii reaction between cycloketones/piperidone and triple-bond containing glycols. The geometries of the obtained molecules were determined using nuclear magnetic resonance (NMR). The electronic structure and geometries of the molecules were studied theoretically using first-principles calculations based on density functional theory. The calculated geometries agree very well with the experimentally measured ones, and also allow us to determine bond lengths, angles and charge distributions inside the molecules. The stability of the OH-radicals located close to the triple bond and the piperidine/cyclohexane rings was proven by both experimental and theoretical analyses. The HOMO/LUMO analysis was done in order to characterize the electron density of t...

  13. (1R*,21S*,22R*,24S*-Methyl ethyl 2-[23-hydroxy-22,24-diphenyl-8,11,14-trioxa-25-azatetracyclo[19.3.1.02,7.015,20]pentacosa-2,4,6,15(20,16,18-hexaen-25-yl]but-2-enedioate

    Directory of Open Access Journals (Sweden)

    Truong Hong Hieu

    2013-07-01

    Full Text Available The title compound, C40H41NO8, is a product of the reduction of the cyclic carbonyl group of the γ-piperidone subunit of the aza-14-crown-4 ether with subsequent re-esterification of its dimethyl butenoate substituent into a monoethyl monomethyl group. The azacrown macrocycle exhibits a bowl conformation with a dihedral angle of 70.82 (5° between the benzene rings fused to it. The piperidine ring adopts a chair conformation and the methyl ethyl ethylenedicarboxylate fragment has a cis conformation, with a dihedral angle of 66.51 (7° between the two carboxylate groups. The ethyl group is disordered over two sites with occupancies of 0.70 (1:0.30 (1. In the crystal, molecules form inversion dimers, via pairs of O—H...O hydrogen bonds, that stack along the a axis.

  14. 2,4-Bis(4-ethoxyphenyl-7-methyl-3-azabicyclo[3.3.1]nonan-9-one

    Directory of Open Access Journals (Sweden)

    V. Ramkumar

    2012-03-01

    Full Text Available The molecule of the title compound, C25H31NO3, exists in a twin-chair conformation with an equatorial orientation of the 4-ethoxyphenyl groups, as observed for its ortho isomer [Parthiban, Ramkumar, Park & Jeong (2011b, Acta Cryst. E67, o1475–o1476]. The methyl and 4-ethoxyphenyl groups are also equatorially oriented on the bicycle, as in the ortho analogue. In particular, although the cyclohexanone ring deviates from an ideal chair, the piperidone ring is closer to an ideal chair, whereas in the ortho isomer both rings are significantly puckered and deviate from ideal chairs. The 4-ethoxyphenyl groups on both sides of the secondary amine group are oriented at an angle of 26.11 (3° with respect to each other, but the 2-ethoxyphenyl groups in the ortho isomer are oriented by less than half this [12.41 (4°]. In contrast to the absence of any significant interactions in the crystal packing of the ortho isomer, the title compound features N—H...O interactions, linking the molecules along the b axis.

  15. Alkynyl-naphthalimide Fluorophores: Gold Coordination Chemistry and Cellular Imaging Applications.

    Science.gov (United States)

    Langdon-Jones, Emily E; Lloyd, David; Hayes, Anthony J; Wainwright, Shane D; Mottram, Huw J; Coles, Simon J; Horton, Peter N; Pope, Simon J A

    2015-07-01

    A range of fluorescent alkynyl-naphthalimide fluorophores has been synthesized and their photophysical properties examined. The fluorescent ligands are based upon a 4-substituted 1,8-naphthalimide core and incorporate structural variations (at the 4-position) to tune the amphiphilic character: chloro (L1), 4-[2-(2-aminoethoxy)ethanol] (L2), 4-[2-(2-methoxyethoxy)ethylamino] (L3), piperidine (L4), morpholine (L5), 4-methylpiperidine (L6), and 4-piperidone ethylene ketal (L7) variants. The amino-substituted species (L2-L7) are fluorescent in the visible region at around 517-535 nm through a naphthalimide-localized intramolecular charge transfer (ICT), with appreciable Stokes' shifts of ca. 6500 cm(-1) and lifetimes up to 10.4 ns. Corresponding two-coordinate Au(I) complexes [Au(L)(PPh3)] were isolated, with X-ray structural studies revealing the expected coordination mode via the alkyne donor. The Au(I) complexes retain the visible fluorescence associated with the coordinated alkynyl-naphthalimide ligand. The ligands and complexes were investigated for their cytotoxicity across a range of cell lines (LOVO, MCF-7, A549, PC3, HEK) and their potential as cell imaging agents for HEK (human embryonic kidney) cells and Spironucleus vortens using confocal fluorescence microscopy. The images reveal that these fluorophores are highly compatible with fluorescence microscopy and show some clear intracellular localization patterns that are dependent upon the specific nature of the naphthalimide substituent.

  16. Synthesis and NMDA receptor affinity of fluorinated dioxadrol analogues.

    Science.gov (United States)

    Banerjee, Ashutosh; Schepmann, Dirk; Wünsch, Bernhard

    2010-06-01

    A series of dioxadrol analogues with fluorine substituents in position 4 of the piperidine ring has been synthesized and pharmacologically evaluated. The key step in the synthesis was the fluorination of diastereomeric piperidones 6a and 6c as well as diastereomeric alcohols 9a and 9c with DAST. The reaction of the alcohols 9a and 9c took place with inversion of configuration. After removal of the Cbz-protective group, the NMDA receptor affinities of the resulting secondary amines 8a, 8c, 12b, and 12d were investigated in receptor binding studies. It was shown that the like-configuration of the ring junction was crucial for high NMDA receptor affinity. An axially oriented fluorine atom in position 4 led to 2-(2,2-diphenyl-1,3-dioxolan-4-yl)-4-fluoropiperidine (12d, WMS-2517) with a K(i)-value of 27nM. The NMDA receptor affinity of 8c (WMS-2513) with an additional fluorine atom in equatorial 4-position was slightly reduced (K(i)=81 nM). Both fluorinated dioxadrol derivatives 8c and 12d showed high selectivity against sigma(1) and sigma(2) receptors as well as the polyamine binding site of NR2B receptors.

  17. Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation.

    Science.gov (United States)

    Zha, Gao-Feng; Zhang, Cheng-Pan; Qin, Hua-Li; Jantan, Ibrahim; Sher, Muhammad; Amjad, Muhammad Wahab; Hussain, Muhammad Ajaz; Hussain, Zahid; Bukhari, Syed Nasir Abbas

    2016-05-15

    A series of new α,β-unsaturated carbonyl-based cyclohexanone derivatives was synthesized by simple condensation method and all compounds were characterized by using various spectroscopic techniques. New compounds were evaluated for their effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). These compounds were also screened for in vitro cytotoxicity and for inhibitory activity for self-induced Aβ1-42 aggregation. The effect of these compounds against amyloid β-induced cytotoxicity was also investigated. The findings of in vitro experiment revealed that most of these compounds exhibited potent inhibitory activity against AChE and self-induced Aβ1-42 aggregation. The compound 3o exhibited best AChE (IC50=0.037μM) inhibitory potential. Furthermore, compound 3o disassembled the Aβ fibrils produced by self-induced Aβ aggregation by 76.6%. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activities as compared to reference drug donepezil. The pre-treatment of cells with synthetic compounds protected them against Aβ-induced cell death by up to 92%. Collectively, these findings suggest that some compounds from this series have potential to be promising multifunctional agents for AD treatment and our study suggest the cyclohexanone derivatives as promising new inhibitors for AChE and BuChE, potentially useful to treat neurodegenerative diseases.

  18. N-(Substituted benzyl)-3,5-bis(benzylidene)-4-piperidones: Synthesis and Preliminary Anti-leukemia Activity (I)%N-(Substituted benzyl)-3,5-bis(benzylidene)-4-piperidones: Synthesis and Preliminary Anti-leukemia Activity (I)

    Institute of Scientific and Technical Information of China (English)

    王静; 孟雯; 倪振杰; 薛思佳

    2011-01-01

    A series of novel N-(substituted benzyl)-3,5-bis(benzylidene)-4-piperidones 5a--50 were synthesized with substituted benzylamines as raw materials via a series of Michael addition, Dieckmann condensation, hydrolysis decarboxylation and aldol condensation. The structures were confirmed by 1↑H NMR, IR, MS techniques and elemental analysis. Assay-based antiproliferative activity study using leukemic cell lines K562 revealed that most of the title compounds have high effectiveness in inhibiting leukemia K562 cells proliferation, among which the compounds 5g (IC50=7.81 μg·mL^-1), 5k (IC50=6.35μg·mL^-1), 51 (IC50=7.20 μg·mL^-1), and 50 (IC50=5.79 μg·mL^-1) have better inhibition activities than standard 5-fluorouracil (IC50=8.56 μg·mL^-1).

  19. Investigation of water and methanol sorption in monovalent- and multivalent-ion-exchanged nafion membranes using electron spin resonance.

    Science.gov (United States)

    Lawton, Jamie S; Budil, David E

    2009-08-06

    Electron spin resonance (ESR) spectroscopy was used to monitor the local environment of 2,2,6,6-tetramethyl-4-piperidone N-oxide (TEMPONE) spin probe in Li(+), Ca(2+), and Al(3+) ion-exchanged Nafion 117 membranes swollen with mixed methanol/water solvent at varying compositions. The (14)N hyperfine splitting, a(N), which reflects the local polarity of the nitroxide probe, remains nearly steady at higher solvent contents but increases substantially at lower solvent contents, reflecting close contact with the ions. The rotational rate (R) of the probe increased with solvent content, depending strongly on the amount of solvent at low contents but increasing more gradually at higher solvent contents, similar to the behavior of previously measured solvent translation diffusion coefficients. The rotational rate data from water-containing membranes were fitted using the Fujita free-volume diffusion model, which indicated that multivalent ions tend to increase the free volume fraction of the polymer while decreasing that of the solvent phase. Methanol-containing membranes exhibited greater variation with different exchange ions, but the data could not be fit using the free-volume model, suggesting that the assumption of two phases underlying the free-volume model might not apply to this case. The difference in the trends of swelling between water and methanol is consistent with previous results that have indicated different patterns of penetration for the two solvents. The results are interpreted in terms of changes in membrane morphology with higher-valence ions.

  20. Antitumor effect of sonodynamically activated pyrrolidine tris-acid fullerene

    Science.gov (United States)

    Iwase, Yumiko; Nishi, Koji; Fujimori, Junya; Fukai, Toshio; Yumita, Nagahiko; Ikeda, Toshihiko; Chen, Fu-shin; Momose, Yasunori; Umemura, Shin-ichiro

    2016-07-01

    In this study, the sonodynamically induced antitumor effect of pyrrolidine tris-acid fullerene (PTF) was investigated. Sonodynamically induced antitumor effects of PTF by focused ultrasound were investigated using isolated sarcoma-180 cells and mice bearing ectopically-implanted colon 26 carcinoma. Cell damage induced by ultrasonic exposure was enhanced by 5-fold in the presence of 80 µM PTF. The combined treatment of ultrasound and PTF suppressed the growth of the implanted colon 26 carcinoma. Ultrasonically induced 2,2,6,6-tetramethyl-4-piperidone-1-oxyl (4oxoTEMPO) production in the presence and absence of PTF was assessed, and it was shown that 80 µM PTF enhanced 4oxoTEMPO production as measured by ESR spectroscopy. Histidine, a reactive oxygen scavenger, significantly reduced cell damage and 4oxoTEMPO generation caused by ultrasonic exposure in the presence of PTF. These results suggest that singlet oxygen is likely to be involved in the ultrasonically induced cell damage enhanced by PTF.

  1. Two-dimensional Fourier transform ESR correlation spectroscopy

    Science.gov (United States)

    Gorcester, Jeff; Freed, Jack H.

    1988-04-01

    We describe our pulsed two-dimensional Fourier transform ESR experiment and demonstrate its applicabilty for the double resonance of motionally narrowed nitroxides. Multiple pulse irradiation of the entire nitroxide spectrum enables the correlation of two precessional periods, allowing observation of cross correlations between hyperfine lines introduced by magnetization transfer in the case of a three-pulse experiment (2D ELDOR), or coherence transfer in the case of a two-pulse experiment (COSY). Cross correlations are revealed by the presence of cross peaks which connect the autocorrelation lines appearing along the diagonal ω1=ω2. The amplitudes of these cross peaks are determined by the rates of magnetization transfer in the 2D ELDOR experiment. The density operator theory for the experiment is outlined and applied to the determination of Heisenberg exchange (HE) rates in 2,2,6,6-tetramethyl-4-piperidone-N-oxyl-d15 (PD-tempone) dissolved in toluene-d8. The quantitative accuracy of this experiment is established by comparison with the HE rate measured from the dependence of the spin echo T2 on nitroxide concentration.

  2. Secondary structure of synthetic oligopeptides

    CERN Document Server

    Martinez-Insua, M

    2000-01-01

    The secondary structure of three hydrophobic peptides P2, PRMo and P4 was studied by a combination of Circular Dichroism (CD), Fourier Transform InfraRed (FTIR) and Photoinduced Electron Transfer (PET). These peptides were fluorescence labelled in the central part of the backbone and contained two modified glutamic acid residues (relative positions i, i+4): one conjugated with the fluorescence methoxynapththalene electron donor (DON) and the other with the piperidone electron acceptor (ACC). The three peptides were synthesised to study the length dependence of the switch between alpha-helix and the 3 sub 1 sub 0 -helix conformations, previously observed for peptide PRM1 (Hungerford et al., Angew. Chem., Int. Ed. Engl., 1996, 35, 326-329). The CD and FTIR data indicated that peptides P2, PRMo and P4 adopt alpha-helical conformation in organic media in the temperature range studied and no conformational switch was detected. Furthermore, a mathematical correlation was observed in the PET data, questioning the ag...

  3. A novel curcumin analog (H-4073 enhances the therapeutic efficacy of cisplatin treatment in head and neck cancer.

    Directory of Open Access Journals (Sweden)

    Bhavna Kumar

    Full Text Available Chemotherapy constitutes the standard modality of treatment for localized head and neck squamous cell carcinomas (HNSCC. However, many patients fail to respond and relapse after this treatments due to the acquisition of chemo-resistance. Therefore, there is an urgent need to develop novel drugs that could reverse the resistant phenotype. Curcumin, the constituent of the spice turmeric has been shown to have anti-inflammatory, anti-oxidant and anti-proliferative properties in several tumor types. However, use of curcumin has been limited due to its poor bio-absorption. Recently, a novel class of curcumin analogs, based on diarylidenylpiperidones (DAP, has been developed by incorporating a piperidone link to the beta-diketone structure and fluoro substitutions on the phenyl groups. In this study, we evaluated the effectiveness of H-4073, a parafluorinated variant of DAP, using both in vitro and in vivo head and neck cancer models. Our results demonstrate that H-4073 is a potent anti-tumor agent and it significantly inhibited cell proliferation in all the HNSCC cell lines tested in a dose-dependent manner. In addition, pretreatment of cisplatin-resistant HNSCC cell lines with H-4073 significantly reversed the chemo-resistance as observed by cell viability assay (MTT, apoptosis assay (Annexin V binding and cleaved caspase-3 (Western blot. H-4073 mediated its anti-tumor effects by inhibiting JAK/STAT3, FAK, Akt and VEGF signaling pathways that play important roles in cell proliferation, migration, survival and angiogenesis. In the SCID mouse xenograft model, H-4073 significantly enhanced the anti-tumor and anti-angiogenesis effects of cisplatin, with no added systemic toxicity. Interestingly, H-4073 inhibited tumor angiogenesis by blocking VEGF production by tumor cells as well as directly inhibiting endothelial cell function. Taken together, our results suggest that H-4073 is a potent anti-tumor agent and it can be used to overcome chemotherapy

  4. Synthesis and antitumor activity in vitro of curcumin analogs%姜黄素类似物合成与体外抗肿瘤活性研究

    Institute of Scientific and Technical Information of China (English)

    刘洋; 许建华; 黄秀旺; 刘锋; 吴梅花

    2011-01-01

    Nineteen curcumin analogs were designed and synthesized front aromatic aldehydes and 4-piperidone by claisen-schmidt condensation. Their structures were characterized by 1H-NMR and MS. Their antitumor activities in vitro were evaluated against K562 and SW1116 tumor cell lines by MTT assay. The results showed that compounds 1,2,3,4,5,9,14,18 had significantly better activity against K562 cells than EF-24(IC50 = l. 58 μmol·L-1). Compounds 7,10,11 were stronger than EF-24(IC50 = 11.7μmol ·L-1)on SW1116.%以芳香醛、4-哌啶酮为原料,Claisen-Schimidt缩合制备3,5-(E)-二亚苄基哌啶-4-酮类化合物.采用MTT法测试目标化合物对人类慢性粒细胞白血病急变细胞K562,人结肠癌细胞SW1 116增殖的抑制活性.化合物1-19的结构经核磁和质谱确证,化合物7、10、11对SW1 116的抑制活性比EF-24强,化合物1-5、9、14、18对K562的抑制活性均比EF-24强.

  5. Photo-excitation of carotenoids causes cytotoxicity via singlet oxygen production

    Energy Technology Data Exchange (ETDEWEB)

    Yoshii, Hiroshi, E-mail: yoshii@nirs.go.jp [Research Center for Radiation Emergency Medicine, National Institute of Radiological Science, Chiba 263-8555 (Japan); Faculty of Medical Sciences, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Yoshii, Yukie, E-mail: yukiey@nirs.go.jp [Molecular Imaging Center, National Institute of Radiological Science, Chiba 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Asai, Tatsuya [Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Faculty of Engineering, University of Fukui, Fukui 910-8507 (Japan); Furukawa, Takako [Molecular Imaging Center, National Institute of Radiological Science, Chiba 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan); Takaichi, Shinichi [Department of Biology, Nippon Medical School, Kawasaki, Kanagawa 211-0063 (Japan); Fujibayashi, Yasuhisa [Molecular Imaging Center, National Institute of Radiological Science, Chiba 263-8555 (Japan); Biomedical Imaging Research Center, University of Fukui, Eiheiji, Fukui 910-1193 (Japan)

    2012-01-06

    Highlights: Black-Right-Pointing-Pointer Some photo-excited carotenoids have photosensitizing ability. Black-Right-Pointing-Pointer They are able to produce ROS. Black-Right-Pointing-Pointer Photo-excited fucoxanthin can produce singlet oxygen through energy transfer. -- Abstract: Carotenoids, natural pigments widely distributed in algae and plants, have a conjugated double bond system. Their excitation energies are correlated with conjugation length. We hypothesized that carotenoids whose energy states are above the singlet excited state of oxygen (singlet oxygen) would possess photosensitizing properties. Here, we demonstrated that human skin melanoma (A375) cells are damaged through the photo-excitation of several carotenoids (neoxanthin, fucoxanthin and siphonaxanthin). In contrast, photo-excitation of carotenoids that possess energy states below that of singlet oxygen, such as {beta}-carotene, lutein, loroxanthin and violaxanthin, did not enhance cell death. Production of reactive oxygen species (ROS) by photo-excited fucoxanthin or neoxanthin was confirmed using a reporter assay for ROS production with HeLa Hyper cells, which express a fluorescent indicator protein for intracellular ROS. Fucoxanthin and neoxanthin also showed high cellular penetration and retention. Electron spin resonance spectra using 2,2,6,6-tetramethil-4-piperidone as a singlet oxygen trapping agent demonstrated that singlet oxygen was produced via energy transfer from photo-excited fucoxanthin to oxygen molecules. These results suggest that carotenoids such as fucoxanthin, which are capable of singlet oxygen production through photo-excitation and show good penetration and retention in target cells, are useful as photosensitizers in photodynamic therapy for skin disease.

  6. Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

    Science.gov (United States)

    Ashraf, Zaman; Alamgeer; Rasool, Raqiqatur; Hassan, Mubashir; Ahsan, Haseeb; Afzal, Samina; Afzal, Khurram; Cho, Hongsik; Kim, Song Ja

    2016-01-01

    Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001) is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06%) of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001). The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug. PMID:28009827

  7. Synthesis, Bioevaluation and Molecular Dynamic Simulation Studies of Dexibuprofen–Antioxidant Mutual Prodrugs

    Directory of Open Access Journals (Sweden)

    Zaman Ashraf

    2016-12-01

    Full Text Available Dexibuprofen–antioxidant conjugates were synthesized with the aim to reduce its gastrointestinal effects. The esters analogs of dexibuprofen 5a–c were obtained by reacting its –COOH group with chloroacetyl derivatives 3a–c. The in vitro hydrolysis data confirmed that synthesized prodrugs 5a–c were stable in stomach while undergo significant hydrolysis in 80% human plasma and thus release free dexibuprofen. The minimum reversion was observed at pH 1.2 suggesting that prodrugs are less irritating to stomach than dexibuprofen. The anti-inflammatory activity of 5c (p < 0.001 is more significant than the parent dexibuprofen. The prodrug 5c produced maximum inhibition (42.06% of paw-edema against egg-albumin induced inflammation in mice. Anti-pyretic effects in mice indicated that prodrugs 5a and 5b showed significant inhibition of pyrexia (p < 0.001. The analgesic activity of 5a is more pronounced compared to other synthesized prodrugs. The mean percent inhibition indicated that the prodrug 5a was more active in decreasing the number of writhes induced by acetic acid than standard dexibuprofen. The ulcerogenic activity results assured that synthesized prodrugs produce less gastrointestinal adverse effects than dexibuprofen. The ex vivo antiplatelet aggregation activity results also confirmed that synthesized prodrugs are less irritant to gastrointestinal mucosa than the parent dexibuprofen. Molecular docking analysis showed that the prodrugs 5a–c interacts with the residues present in active binding sites of target protein. The stability of drug–target complexes is verified by molecular dynamic simulation study. It exhibited that synthesized prodrugs formed stable complexes with the COX-2 protein thus support our wet lab results. It is therefore concluded that the synthesized prodrugs have promising pharmacological activities with reduced gastrointestinal adverse effects than the parent drug.

  8. An EPR line shape study of anisotropic rotational reorientation and slow tumbling in liquid and frozen jojoba oil

    Science.gov (United States)

    Hwang, J. S.; Al-Rashid, W. A.

    Spin probe investigation of jojoba oil was carried out by electron paramagnetic rresonance (EPR) spectroscopy. The spin probe used was 2,2,6,6-tetramethyl-4-piperidone- N-oxide. The EPR line shape studies were carried out in the lower temperature range of 192 to 275 K to test the applicability of the stochastic Liouville theory in the simulation of EPR line shapes where earlier relaxation theories do not apply. In an earlier study, this system was analysed by employing rotational diffusion at the fast-motional region. The results show that PD-Tempone exhibits asymmetric rotational diffusion with N = 3.3 at an axis z'= Y in the plane of the molecule and perpendicular to the NO bond direction. In this investigation we have extended the temperature range to lower temperatures and observed slow tumbling EPR spectra. It is shown that the stochastic Liouville method can be used to simulate all but two of the experimentally observed EPR spectra in the slow-motional region and details of the slow-motional line shape are sensitive to the anisotropy of rotation and showed good agreement for a moderate jump model. From the computer simulation of EPR line shapes it is found that the information obtained on τ R, and N in the motional-narrowing region can be extrapolated into the slow-tumbling region. It is also found that ln (τ R) is linear in 1/ T in the temperature range studied and the resulting activation energy for rotation is 51 kJ/mol. The two EPR spectra at 240 and 231 K were found to exhibit the effects of anisotropic viscosity observed by B IRELL for nitroxides oriented in tubular cavities in inclusion crystals in which the molecule is free to rotate about the long axis but with its rotation hindered about the other two axes because of the cavity geometry. These results proved that the slow-tumbling spectra were very sensitive to the effects of anisotropy in the viscosity.

  9. Differentiation of Boc-protected alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptide positional isomers by electrospray ionization tandem mass spectrometry.

    Science.gov (United States)

    Raju, G; Ramesh, V; Srinivas, R; Sharma, G V M; Shoban Babu, B

    2010-06-01

    Two new series of Boc-N-alpha,delta-/delta,alpha- and beta,delta-/delta,beta-hybrid peptides containing repeats of L-Ala-delta(5)-Caa/delta(5)-Caa-L-Ala and beta(3)-Caa-delta(5)-Caa/delta(5)-Caa-beta(3)-Caa (L-Ala = L-alanine, Caa = C-linked carbo amino acid derived from D-xylose) have been differentiated by both positive and negative ion electrospray ionization (ESI) ion trap tandem mass spectrometry (MS/MS). MS(n) spectra of protonated isomeric peptides produce characteristic fragmentation involving the peptide backbone, the Boc-group, and the side chain. The dipeptide positional isomers are differentiated by the collision-induced dissociation (CID) of the protonated peptides. The loss of 2-methylprop-1-ene is more pronounced for Boc-NH-L-Ala-delta-Caa-OCH(3) (1), whereas it is totally absent for its positional isomer Boc-NH-delta-Caa-L-Ala-OCH(3) (7), instead it shows significant loss of t-butanol. On the other hand, second isomeric pair shows significant loss of t-butanol and loss of acetone for Boc-NH-delta-Caa-beta-Caa-OCH(3) (18), whereas these are insignificant for its positional isomer Boc-NH-beta-Caa-delta-Caa-OCH(3) (13). The tetra- and hexapeptide positional isomers also show significant differences in MS(2) and MS(3) CID spectra. It is observed that 'b' ions are abundant when oxazolone structures are formed through five-membered cyclic transition state and cyclization process for larger 'b' ions led to its insignificant abundance. However, b(1)(+) ion is formed in case of delta,alpha-dipeptide that may have a six-membered substituted piperidone ion structure. Furthermore, ESI negative ion MS/MS has also been found to be useful for differentiating these isomeric peptide acids. Thus, the results of MS/MS of pairs of di-, tetra-, and hexapeptide positional isomers provide peptide sequencing information and distinguish the positional isomers.

  10. Liposome-encapsulated EF24-HP{beta}CD inclusion complex: a preformulation study and biodistribution in a rat model

    Energy Technology Data Exchange (ETDEWEB)

    Agashe, H.; Lagisetty, P.; Sahoo, K.; Bourne, D. [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States); Grady, B. [School of Chemical, Biological and Materials Engineering (United States); Awasthi, V., E-mail: vawasthi@ouhsc.edu [University of Oklahoma Health Sciences Center, Department of Pharmaceutical Sciences (United States)

    2011-06-15

    3,5-Bis(2-fluorobenzylidene)-4-piperidone (EF24) is an anti-proliferative diphenyldifluoroketone analog of curcumin with more potent activity. The authors describe a liposome preparation of EF24 using a 'drug-in-CD-in liposome' approach. An aqueous solution of EF24 and hydroxypropyl-{beta}-cyclodextrin (HP{beta}CD) inclusion complex (IC) was used to prepare EF24 liposomes. The liposome size was reduced by a combination of multiple freeze-thaw cycles. Co-encapsulation of glutathione inside the liposomes conferred them with the capability of labeling with imageable radionuclide Tc-99m. Phase solubility analysis of EF24-HP{beta}CD mixture provided k{sub 1:1} value of 9.9 M{sup -1}. The enhanced aqueous solubility of EF24 (from 1.64 to 13.8 mg/mL) due to the presence of HP{beta}CD helped in the liposome preparation. About 19% of the EF24 IC was encapsulated inside the liposomes (320.5 {+-} 2.6 nm) by dehydration-rehydration technique. With extrusion technique, the size of 177 {+-} 6.5 nm was obtained without any effect on encapsulation efficiency. The EF24-liposomes were evaluated for anti-proliferative activity in lung adenocarcinoma H441 and prostate cancer PC-3 cells. The EF24-liposomes demonstrated anti-proliferative activity superior to that of plain EF24 at 10 {mu}M dose. When injected in rats, the Tc-99m-labeled EF24-liposomes cleared from blood with an {alpha}-t{sub 1/2} of 21.4 min and {beta}-t{sub 1/2} of 397 min. Tissue radioactivity counting upon necropsy showed that the majority of clearance was due to the uptake in liver and spleen. The results suggest that using 'drug-in-CD-in liposome' approach is a feasible strategy to formulate an effective parenteral preparation of EF24. In vitro studies show that the liposomal EF24 remains anti-proliferative, while presenting an opportunity to image its biodistribution.

  11. Saturation recovery EPR and ELDOR at W-band for spin labels

    Science.gov (United States)

    Froncisz, Wojciech; Camenisch, Theodore G.; Ratke, Joseph J.; Anderson, James R.; Subczynski, Witold K.; Strangeway, Robert A.; Sidabras, Jason W.; Hyde, James S.

    2008-08-01

    A reference arm W-band (94 GHz) microwave bridge with two sample-irradiation arms for saturation recovery (SR) EPR and ELDOR experiments is described. Frequencies in each arm are derived from 2 GHz synthesizers that have a common time-base and are translated to 94 GHz in steps of 33 and 59 GHz. Intended applications are to nitroxide radical spin labels and spin probes in the liquid phase. An enabling technology is the use of a W-band loop-gap resonator (LGR) [J.W. Sidabras, R.R. Mett, W. Froncisz, T.G. Camenisch, J.R. Anderson, J.S. Hyde, Multipurpose EPR loop-gap resonator and cylindrical TE 011 cavity for aqueous samples at 94 GHz, Rev. Sci. Instrum. 78 (2007) 034701]. The high efficiency parameter (8.2 GW -1/2 with sample) permits the saturating pump pulse level to be just 5 mW or less. Applications of SR EPR and ELDOR to the hydrophilic spin labels 3-carbamoyl-2,2,5,5-tetra-methyl-3-pyrroline-1-yloxyl (CTPO) and 2,2,6,6,-tetramethyl-4-piperidone-1-oxyl (TEMPONE) are described in detail. In the SR ELDOR experiment, nitrogen nuclear relaxation as well as Heisenberg exchange transfer saturation from pumped to observed hyperfine transitions. SR ELDOR was found to be an essential method for measurements of saturation transfer rates for small molecules such as TEMPONE. Free induction decay (FID) signals for small nitroxides at W-band are also reported. Results are compared with multifrequency measurements of T1e previously reported for these molecules in the range of 2-35 GHz [J.S. Hyde, J.-J. Yin, W.K. Subczynski, T.G. Camenisch, J.J. Ratke, W. Froncisz, Spin label EPR T 1 values using saturation recovery from 2 to 35 GHz. J. Phys. Chem. B 108 (2004) 9524-9529]. The values of T1e decrease at 94 GHz relative to values at 35 GHz.

  12. Involvement of both Type I and Type II mechanisms in Gram-positive and Gram-negative bacteria photosensitization by a meso-substituted cationic porphyrin

    Energy Technology Data Exchange (ETDEWEB)

    Ergaieg, Karim; Seux, Rene [Laboratoire d' Etude et de Recherche en Environnement et Sante, National School of Public Health, Av. Pr. Leon Bernard, CS 74312, Rennes 35043 (France); Chevanne, Martine; Cillard, Josiane [Laboratoire de Biologie Cellulaire et Vegetale, UPRES 3891, UFR des Sciences Pharmaceutiques et Biologiques, University of Rennes 1, 2 Av. Pr. Leon Bernard, CS 34317, Rennes 35043 (France)

    2008-12-15

    A meso-substituted cationic porphyrin (TMPyP) showed a photocytotoxicity against Gram-positive and Gram-negative bacteria. In order to determine the mechanism involved in the phototoxicity of this photosensitizer, electron paramagnetic resonance (EPR) experiments with 2,2,6,6-tetramethyl-4-piperidone (TEMP), a specific probe for singlet oxygen, and the spin-trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) were carried out with illuminated TMPyP. An EPR signal characteristic of TEMP-singlet oxygen (TEMPO) adduct formation was observed, which could be ascribed to singlet oxygen ({sup 1}O{sub 2}) generated by TMPyP photosensitization. The signal for the DMPO spin adduct of superoxide anion (DMPO-OOH) was observed in DMSO solution but not in aqueous conditions. However, an EPR spectrum characteristic of the DMPO-hydroxyl radical spin adduct (DMPO-OH) was observed in aqueous conditions. The obtained results testify a primary hydroxyl radical ({sup .}OH) generation probably from superoxide anion (O{sub 2} {sup x} {sup -})via the Fenton reaction and/or via Haber-Weiss reaction. Gram-positive and Gram-negative bacteria inactivation by TMPyP photosensitization predominantly involved Type II reactions mediated by the formation of {sup 1}O{sub 2}, as demonstrated by the effect of quenchers for {sup 1}O{sub 2} and scavengers for {sup .}OH (sodium azide, thiourea, and dimethylsulphoxide). Participation of other active oxygen species cannot however be neglected since Type I reactions also had a significant effect, particularly for Gram-negative bacteria. For Gram-negative bacteria the photoinactivation rate was lower in the presence of superoxide dismutase, a specific O{sub 2} {sup x} {sup -} scavenger, and/or catalase, an enzyme which specifically eliminates H{sub 2}O{sub 2}, but was unchanged for Gram-positive bacteria. The generation of {sup 1}O{sub 2}, O{sub 2} {sup x} {sup -} and {sup .}OH by TMPyP photosensitization indicated that TMPyP maintained a photodynamic activity in