- Antiproliferative and antibacterial activity of some glutarimide derivatives
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Antiproliferative and antibacterial activities of nine glutarimide derivatives (1–9) were reported. Cytotoxicity of compounds was tested toward three human cancer cell lines, HeLa, K562 and MDA-MB-453 by MTT assay. Compound 7 (2-benzyl-2-azaspiro[5.11]heptadecane-1,3,7-trione), containing 12-membered ketone ring, was found to be the most potent toward all tested cell lines (IC50 = 9–27 μM). Preliminary screening of antibacterial activity by a disk diffusion method showed that Gram-positive bacteria were more susceptible to the tested compounds than Gram-negative bacteria. Minimum inhibitory concentration (MIC) determined by a broth microdilution method confirmed that compounds 1, 2, 4, 6–8 and 9 inhibited the growth of all tested Gram-positive and some of the Gram-negative bacteria. The best antibacterial potential was achieved with compound 9 (ethyl 4-(1-benzyl-2,6-dioxopiperidin-3-yl)butanoate) against Bacillus cereus (MIC 0.625 mg/mL; 1.97 × 10?3mol/L). Distinction between more and less active/inactive compounds was assessed from the pharmacophoric patterns obtained by molecular interaction fields.
- Popovi?-Djordjevi?, Jelena B.,Klaus, Anita S.,?i?ak, ?eljko S.,Mati?, Ivana Z.,Drakuli?, Branko J.
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- Synthesis of 5,12-DiHETE Derivative by Palladium-Catalyzed Ternary Coupling between Vinylic Halide, a Vinylic Tin Compound, and Norbornadiene
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A racemic 5,12-DiHETE-8,9-cyclopentadiene Diels-Alder adduct was prepared by palladium-catalyzed ternary coupling between vinylic halide, a vinylic tin compound, and norbornadiene in good yields.Both the halide and tin chain were synthesized in excellent yields by three and four steps, respectively.
- Oda, Hiroshi,Kobayashi, Tohru,Kosugi, Masanori,Migita, Toshihiko
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Read Online
- A possible improvement for structure-based drug design illustrated by the discovery of a Tat HIV-1 inhibitor
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The HIV-1 Tat protein is a promising target for AIDS therapy, due to its extra-cellular roles against the immune system. From the 2D-NMR structure of Tat, we have designed molecules, called TDS, able to bind to Tat and inhibit HIV-1 replication in vitro. This new family of antivirals is composed of a triphenylene aromatic ring substituted with at least one carbon chain bearing a succinimide group. These ligands are prepared from triphenylene or 2,6,10-trimethylphenylene in 3-6 steps depending on the target molecule.
- Montembault, Mickael,Vo-Thanh, Giang,Deyine, Abdallah,Fargeas, Valerie,Villieras, Monique,Adjou, Ane,Dubreuil, Didier,Esquieu, Didier,Gregoire, Catherine,Opi, Sandrine,Peloponese, Jean-Marie,Campbell, Grant,Watkins, Jennifer,De Mareuil, Jean,Aubertin, Anne-Marie,Bailly, Christian,Loret, Erwann,Lebreton, Jacques
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- OBTENTION DE LA LACTONE DE PRELOG-DJERASSI ET D'AUTRES δ-LACTONES PAR ADDITION DU PENTENYLTRIMETHYLSILANE SUR DES DERIVES DE L'ANHYDRIDE GLUTARIQUE
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Addition of trans-3-trimethylsilyl-pent-2-ene to derivatives of glutaric anhydride and meso-2,4-dimethylglutaric anhydride leads to precursors of the PRELOG-DJERASSI lactone and related δ-lactones.
- Santelli-Rouvier, par Christiane
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- Computer-aided identification of new histone deacetylase 6 selective inhibitor with anti-sepsis activity
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Histone deacetylase (HDAC) inhibitors have been recognized as promising approaches to the treatment of various human diseases including cancer, inflammation, neurodegenerative diseases, and metabolic disorders. Several pan-HDAC inhibitors are currently approved only as anticancer drugs. Interestingly, SAHA (vorinostat), one of clinically available pan-HDAC inhibitors, shows an anti-inflammatory effect at concentrations lower than those required for inhibition of tumor cell growth. It was also reported that HDAC6 selective inhibitor tubastatin A has anti-inflammatory and anti-rheumatic effect. In our efforts to develop novel HDAC inhibitors, we rationally designed various HDAC inhibitors based on the structures of two hit compounds identified by virtual screening of chemical database. Among them, 9a ((E)-N-hydroxy-4-(2-styrylthiazol-4-yl)butanamide) was identified as a HDAC6 selective inhibitor (IC50 values of 0.199 μM for HDAC6 versus 13.8 μM for HDAC1), and it did not show significant cytotoxicity against HeLa cells. In vivo biological evaluation of 9a was conducted on a lipopolysaccharide (LPS)-induced mouse model of sepsis. The compound 9a significantly improved 40% survival rate (P = 0.0483), and suppressed the LPS-induced increase of TNF-α and IL-6 mRNA expression in the liver of mice. Our study identified novel HDAC6 selective inhibitor 9a, which may serve as a potential lead for the development of anti-inflammatory or anti-sepsis agents.
- Yoo, Jakyung,Kim, So-Jin,Son, Dohyun,Seo, Heewon,Baek, Seung Yeop,Maeng, Cheol-Young,Lee, Changsik,Kim, In Su,Jung, Young Hoon,Lee, Sun-Mee,Park, Hyun-Ju
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- Synthesis of 10,11-dihydroleukotriene B4 metabolites via a nickel- catalyzed coupling reaction of cis-bromides and trans-alkenyl borates
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Synthesis of 10,11-dihydro-, 10,11,14,15-tetrahydro-, and 10,11-dihydro- 12-oxoleukotriene B4 compounds (2, 4, 5) was accomplished stereoselectively by using the nickel-catalyzed coupling reaction illustrated in Scheme 1. The C(1)-C(7) fragments, TBS ether 10a for 2 and 4 and ethyoxyethyl (EE) ether 10b for 5, were prepared in enantiomerically pure forms (>99% ee) by a modified literature procedure (ref 11a). On the other hand, boronate esters 11a and 11b, which correspond to the C(8)-C(20) parts of 2 and 4, respectively, were synthesized from (R)-epichlorohydrin of 99% ee. Briefly, 18 was converted into acetylenes 24 and 32 through epoxide ring-opening with LiC≡CC5H11/BF3·OEt2 or C7H15MgBr/CuCN. Hydroboration of these acetylenes with (+)-(Ipc)2BH followed by reaction with MeCHO afforded the corresponding diethyl boronates, which upon ligand exchange with Me2C(CH2OH)2 furnished boronate esters 11a and 11b in 75% and 77% yields, respectively. In a similar manner, racemic boronate ester rac-11a, an intermediate for synthesis of 5, was prepared from racemic epichlorohydrin. For synthesis of 2, borate 25 was generated from 11a (1.5 equiv) and MeLi (1.6 equiv). Without isolation, 25 was submitted to reaction with 10a (1 equiv) in the presence of a Ni(0) species at room temperature overnight to afford 26, which upon treatment with TBAF furnished 2 in 64% yield from 10a. Similarly, 11b and 10a furnished 4 in good yield. To synthesize 5, rac-11a and EE ether 10b were joined by the coupling reaction to produce 39, which was transformed into 40 by desilylation with TBAF. After hydrolysis of 40, oxidation with PDC followed by deprotection of the EE group furnished 5 in 36% yield from 40. In addition, 2 was converted into amide 3 in 92% yield.
- Nakayama, Yuji,Kumar, G. Biju,Kobayashi, Yuichi
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- Neutrophil-Selective Fluorescent Probe Development through Metabolism-Oriented Live-Cell Distinction
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Human neutrophils are the most abundant leukocytes and have been considered as the first line of defence in the innate immune system. Selective imaging of live neutrophils will facilitate the in situ study of neutrophils in infection or inflammation events as well as clinical diagnosis. However, small-molecule-based probes for the discrimination of live neutrophils among different granulocytes in human blood have yet to be reported. Herein, we report the first fluorescent probe NeutropG for the specific distinction and imaging of active neutrophils. The selective staining mechanism of NeutropG is elucidated as metabolism-oriented live-cell distinction (MOLD) through lipid droplet biogenesis with the help of ACSL and DGAT. Finally, NeutropG is applied to accurately quantify neutrophil levels in fresh blood samples by showing a high correlation with the current clinical method.
- Gao, Min,Lee, Sun Hyeok,Park, Sang Hyuk,Ciaramicoli, Larissa Miasiro,Kwon, Haw-Young,Cho, Heewon,Jeong, Joseph,Chang, Young-Tae
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supporting information
p. 23743 - 23749
(2021/10/14)
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- Molecularly Imprinted Polymers with Enhanced Selectivity Based on 4-(Aminomethyl)pyridine-Functionalized Poly(2-oxazoline)s for Detecting Hazardous Herbicide Contaminants
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The detection of hazardous compounds is of importance to control (drinking) water quality. Here, we report the development of poly(2-oxazoline)-based molecularly imprinted polymers (MIPs) for the detection of 2,4,5-trichlorophenoxyacetic acid (2,4,5-T). In view of enhanced selectivity of the MIPs, it was hypothesized that incorporation of pyridine groups would lead to stronger interactions with 2,4,5-T. The synthesis of 4-(aminomethyl)pyridine (4-AMP)-functionalized poly(2-methoxycarbonylpropyl-2-oxazoline)s with various degrees of modification was, therefore, investigated via stoichiometric and kinetic control over the functionalization degree. The molecular imprinting of 2,4,5-T is performed by direct amidation of the methyl ester side chains with diethylenetriamine. The experimental data of 2,4,5-T adsorption were interpreted with various models to quantify the adsorption thermodynamics and kinetics. The best fit was obtained for a single-site Langmuir model, indicating uniform binding site energies. A further investigation shows that the maximum adsorption capacity is reached at low 4-AMP modification degrees, whereas greater adsorption energies and higher selectivities are observed for higher 4-AMP modification degrees. Finally, the developed 4-AMP-modified MIP adsorbents were successfully used for quantification of 2,4,5-T by direct analysis with ambient mass spectrometry. In comparison with the pure analyte solution, the detection limits decreased by three orders of magnitude.
- Ceg?owski, Micha?,D'Hooge, Dagmar R.,De Smet, Lieselot,Hoogenboom, Richard,Marien, Yoshi W.,Schroeder, Grzegorz,Smeets, Sander
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- New compounds for a good old class: Synthesis of two Β-lactam bearing cephalosporins and their evaluation with a multidisciplinary approach
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Antimicrobial resistance is spreading massively in the world and is becoming one of the main health threats of the 21st century. One of the possible strategies to overcome this problem is to modify the known classes of antibiotics in a rational way, with the aim of tuning their efficacy. In this paper, we present the synthesis and the evaluation of the biological activity of a series of two β-lactam bearing cephalosporin derivatives, in which an additional isolated azetidinone ring, bearing different substituents, is joined to the classical cephalosporanic nucleus by a chain of variable length. A computational approach has been also applied in order to predict the molecular interactions between some representative derivatives and selected penicillin-binding proteins, the natural targets of β-lactam antibiotics. All these derivatives are active against Gram-positive bacteria, with MIC100 comparable or even better than that of the reference antibiotic ceftriaxone, and show no or very low cytotoxic activity on different cell lines. Overall, these molecules appear to be able to exert their activity in particular against microorganisms belonging to some of the species more involved in the development of multidrug resistance.
- Vigliotta, Giovanni,Giordano, Deborah,Verdino, Anna,Caputo, Ivana,Martucciello, Stefania,Soriente, Annunziata,Marabotti, Anna,De Rosa, Margherita
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supporting information
(2020/01/22)
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- Design, synthesis and biological evaluation of novel indazole-based derivatives as potent HDAC inhibitors via fragment-based virtual screening
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Based on fragment-based virtual screening and bioisoterism strategies, novel indazole and pyrazolo[3,4-b] pyridine derivatives as HDACs inhibitors were designed, synthesized and evaluated. Most of these compounds displayed good to excellent inhibitory activities against HDACs, especially compounds 15k and 15m were identified as potent inhibitors of HDAC1 (IC50 = 2.7 nM and IC50 = 3.1 nM), HDAC2 (IC50 = 4.2 nM and IC50 = 3.6 nM) and HDAC8 (IC50 = 3.6 nM and IC50 = 3.3 nM). Further anti-proliferation assays revealed that compounds 15k and 15m showed better anti-proliferative activities against HCT-116 and HeLa cells than positive control SAHA. The western blot analysis results indicated that compounds 15k and 15m noticeably up-regulated the level of acetylated α-tubulin and histone H3. In addition, the two compounds 15k and 15m could arrest cell cycle in G2/M phase and promote cell apoptosis, which was similar as the reference compound SAHA. Through the molecular docking and dynamic studies, the potent HDAC inhibitory activities mainly caused by van der Waals and electrostatic interactions with the HDACs.
- Gao, Liang,Gao, Lina,He, Fengjun,Hu, Lihong,Kang, Di,Liu, Jian,Wang, Ping,Wen, Yu,Zhou, Jingxian
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- Compound and preparation method and application thereof
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The invention relates to a compound as well as a preparation method and application thereof, in particular to a compound for treating cancer as well as a preparation method and application thereof. The structure of the compound is shown as a formula (I). The compound provided by the invention can inhibit the growth of human breast cancer, lung cancer and colorectal cancer tumor cells, can be usedfor treating breast cancer, lung cancer and colorectal cancer, can be used for treating breast cancer, and is especially suitable for treating triple-negative breast cancer.
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Paragraph 0076; 0080-0081
(2020/07/02)
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- Azetidinone derivatives and its preparation method and application
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The invention discloses azacyclobutanone derivatives which are compounds as shown in the formula (I) and medicinal salts thereof. The invention further discloses a preparation method and application of the azacyclobutanone derivatives. The azacyclobutanone derivatives disclosed by the invention can be used for treating or preventing atherosclerosis or lowering plasma cholesterol level, and has strong plasma cholesterol reducing activity and wide market prospect.
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Paragraph 0056; 0057
(2017/03/28)
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- COMPOUND FOR PROMOTING APOPTOSIS OF CANCER CELLS AND A PHARMACEUTICAL COMPOSITION CONTAINING THE SAME AND USES THEREOF
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The present invention provides a compound of Formula (I) and a salt thereof, wherein, m is an integer of 2 to 7, and R is independently at least one selected from the group consisting of hydrogen and C1-C20 alkyl. The compound promotes apoptosis in cancer cell and inhibits its growth. The present invention also provides a pharmaceutical composition which comprises the compound of Formula (I), a salt thereof and a pharmaceutically acceptable carrier. The present invention further provides a method for production of the pharmaceutical composition used for treating cancer.
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Paragraph 0064
(2016/04/20)
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- BIFUNCTIONAL CYTOTOXIC AGENTS CONTAINING THE CTI PHARMACOPHORE
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The present invention is directed to novel bifunctional CTI-CTI and CBI-CTI dimers of the formula: [in-line-formulae]F1-L1-T-L2-F2 [/in-line-formulae] where F1, L1, T, L2 and F2 are as defined herein, useful for the treatment for proliferative diseases, where the inventive dimers can function as stand-alone drugs, payloads in antibody-drug-conjugates (ADCs), and linker-payload compounds useful in connection with the production or administration of such ADCs; and to compositions including the aforementioned dimers, linker-payloads and ADCs, and methods for using these dimers, linker-payloads and ADCs, to treat pathological conditions including cancer.
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Paragraph 0336; 0337
(2016/10/11)
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- Base-Promoted/Gold-Catalyzed Intramolecular Highly Selective and Controllable Detosylative Cyclization
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A highly selective, controllable and synthetically useful base-promoted intramolecular detosylative cyclization of bis-N-tosylhydrazones has been achieved, affording N-containing heterocycles and cyclic olefins under transition-metal-free or gold-catalyzed procedures, respectively. Moreover, an effective and practical metal-free or gold-catalyzed approach to synthesize polycyclic aromatic compounds is also reported. Basic cyclizations: A highly selective, controllable, and synthetically useful base-promoted intramolecular detosylative cyclization of bis-N-tosylhydrazones affords N-containing heterocycles and cyclic olefins under transition-metal-free or gold-catalyzed procedures, respectively. Moreover, an effective and practical metal-free or gold-catalyzed approach to synthesize polycyclic aromatic compounds is also reported.
- Zhu, Chenghao,Qiu, Lin,Xu, Guangyang,Li, Jian,Sun, Jiangtao
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supporting information
p. 12871 - 12875
(2015/09/07)
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- Metal-free decarboxylative Hetero-Diels-Alder synthesis of 3-hydroxypyridines: A rapid access to N-fused bicyclic hydroxypiperidine scaffolds
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A complete experimental and theoretical study of the thermally controlled metal-free decarboxylative hetero-Diels-Alder (HDA) reaction of 5-alkoxyoxazoles with acrylic acid is reported. This strategy offers a new entry to valuable 2,6-difunctionalized 3-hydroxypyridines from readily available 2- and 4-disubstituted 5-alkoxyoxazoles. The reaction conditions proved compatible with, among others, ketone, amide, ester, ether, and nitrile groups. The broad functional group tolerance of the protocol allows a rapid and versatile access to both hydroxyindolizidine and hydroxyquinolizidine derivatives via a pyridine dearomatization strategy.
- Jouanno, Laurie-Anne,Di Mascio, Vincent,Tognetti, Vincent,Joubert, Laurent,Sabot, Cyrille,Renard, Pierre-Yves
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p. 1303 - 1319
(2014/03/21)
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- Optimization of gefitinib analogues with potent anticancer activity
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The interactions of gefitinib (Iressa) in EGFR are hydrogen bonding and van der Waals forces through quinazoline and aniline rings. However the morpholino group of gefitinib is poorly ordered due to its weak electron density. A series of novel piperazino analogues of gefitinib where morpholino group substituted with various piperazino groups were designed and synthesized. Most of them indicated significant anti-cancer activities against human cancer cell lines. In particular, compounds 52-54 showed excellent potency against cancer cells. Convergent synthetic approach has been developed for the synthesis of gefitinib intermediate which can lead to gefitinib as well as numerous analogues.
- Yin, Kai-Hao,Hsieh, Yi-Han,Sulake, Rohidas S.,Wang, Su-Pei,Chao, Jui-I.,Chen, Chinpiao
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supporting information
p. 5247 - 5250
(2015/01/08)
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- Insights into soluble guanylyl cyclase activation derived from improved heme-mimetics
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Recently, the structure of BAY 58-2667 bound to the Nostoc sp. H-NOX domain was published. On the basis of this structural information, we designed BAY 58-2667 derivatives and tested their effects on soluble guanylyl cyclase (sGC) activity. Derivative 20 activated sGC 4.8-fold more than BAY 58-2667. Co-crystallization of 20 with the Ns H-NOX domain revealed that the increased conformational distortion at the C-terminal region of αF helix containing 110-114 residues contributes to the higher activation triggered by 20.
- Von Wantoch Rekowski, Margarete,Kumar, Vijay,Zhou, Zongmin,Moschner, Johann,Marazioti, Antonia,Bantzi, Marina,Spyroulias, Georgios A.,Van Den Akker, Focco,Giannis, Athanassios,Papapetropoulos, Andreas
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supporting information
p. 8948 - 8952
(2013/12/04)
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- Use of a semihollow-shaped triethynylphosphane ligand for efficient formation of six- and seven-membered ring ethers through gold(I)-catalyzed cyclization of hydroxy-tethered propargylic esters
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The formation of six- and seven-membered ring ethers from hydroxy-tethered propargylic esters was efficiently catalyzed by a cationic gold(I) complex with a semihollow-shaped triethynylphosphane ligand. This gold catalysis showed a tolerance toward the reactions of primary, secondary, and tertiary alcohol substrates with various substitution patterns. A sterically congested 2,2,6,6-tetraalkyl-substituted tetrahydropyran derivative as well as 6,6- and 7,6-fused bicyclic diethers were obtained in useful yields. In addition, the gold catalysis was applicable to the reaction of a sulfonamide-tethered propargylic ester to give a piperidine derivative. Copyright
- Ito, Hideto,Harada, Ayumi,Ohmiya, Hirohisa,Sawamura, Masaya
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supporting information
p. 647 - 652
(2013/04/10)
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- Discovery of LFF571: An investigational agent for Clostridium difficile infection
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Clostridium difficile (C. difficile) is a Gram positive, anaerobic bacterium that infects the lumen of the large intestine and produces toxins. This results in a range of syndromes from mild diarrhea to severe toxic megacolon and death. Alarmingly, the prevalence and severity of C. difficile infection are increasing; thus, associated morbidity and mortality rates are rising. 4-Aminothiazolyl analogues of the antibiotic natural product GE2270 A (1) were designed, synthesized, and optimized for the treatment of C. difficile infection. The medicinal chemistry effort focused on enhancing aqueous solubility relative to that of the natural product and previous development candidates (2, 3) and improving antibacterial activity. Structure-activity relationships, cocrystallographic interactions, pharmacokinetics, and efficacy in animal models of infection were characterized. These studies identified a series of dicarboxylic acid derivatives, which enhanced solubility/efficacy profile by several orders of magnitude compared to previously studied compounds and led to the selection of LFF571 (4) as an investigational new drug for treating C. difficile infection.
- Lamarche, Matthew J.,Leeds, Jennifer A.,Amaral, Adam,Brewer, Jason T.,Bushell, Simon M.,Deng, Gejing,Dewhurst, Janetta M.,Ding, Jian,Dzink-Fox, Joanne,Gamber, Gabriel,Jain, Akash,Lee, Kwangho,Lee, Lac,Lister, Troy,McKenney, David,Mullin, Steve,Osborne, Colin,Palestrant, Deborah,Patane, Michael A.,Rann, Elin M.,Sachdeva, Meena,Shao, Jian,Tiamfook, Stacey,Trzasko, Anna,Whitehead, Lewis,Yifru, Aregahegn,Yu, Donghui,Yan, Wanlin,Zhu, Qingming
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supporting information; experimental part
p. 2376 - 2387
(2012/06/01)
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- Design, synthesis and preliminary bioactivity studies of 1,3,4-thiadiazole hydroxamic acid derivatives as novel histone deacetylase inhibitors
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Histone deacetylase (HDAC) inhibitors have emerged as a new class of anticancer agents, targeting the biological processes including cell cycle, apoptosis and differentiation. In the present study, a series of 1,3,4-thiadiazole based hydroxamic acids were developed as potent HDAC inhibitors. Some of them showed good inhibitory activity in HDAC enzyme assay and potent growth inhibition in some tumor cell lines. Among them, compound 6i (IC50 = 0.089 μM), exhibited better inhibitory effect compared with SAHA (IC50 = 0.15 μM).
- Guan, Peng,Sun, Feng'E,Hou, Xuben,Wang, Feng,Yi, Fan,Xu, Wenfang,Fang, Hao
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experimental part
p. 3865 - 3872
(2012/08/27)
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- ESTERAMIDE SOLVENTS/COALESCING AGENTS IN PHYTOSANITARY, CLEANING, DEGREASING, STRIPPING, LUBRICATING, COATING, AND PIGMENT/INK COMPOSITIONS
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Esteramide compounds are useful solvents/coalescing agents for a variety of phytosanitary, cleaning, degreasing, stripping, lubricating, coating and pigment/ink compositions.
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Page/Page column 18
(2011/07/29)
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- Synthesis of acylsilanes by palladium-catalyzed cross-coupling reaction of thiol esters and silylzinc chlorides
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An acylsilane synthesis by a Pd-catalyzed cross-coupling reaction of thiol esters and silylzinc chlorides was developed. S-Phenyl thiol esters with a variety of functional groups were converted to corresponding acylsilanes.
- Azuma, Hiroki,Okano, Kentaro,Tokuyama, Hidetoshi
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supporting information; experimental part
p. 959 - 961
(2011/12/05)
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- Synthesis and biological evaluation of Ezetimibe analogs as possible cholesterol absorption inhibitors
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In order to investigate the SAR of Ezetimibe analogs for cholesterol absorption inhibitions, amide group and electron-deficient pyridine ring were introduced to the C-(3) carbon chain of Ezetimibe. Eight new derivatives of the 2- azetidinone cholesterol absorption inhibitors have been synthesized, and all of them were enantiomerically pure. All the new compounds were evaluated for their activity to inhibit cholesterol absorption in hamsters, and most of them showed comparable effects in lowering the levels of total cholesterol in the serum.
- Wang, Yubin,Haiqian,Huang, Wenlong,Zhang, Huibin,Zhou, Jinpei
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scheme or table
p. 500 - 505
(2012/05/19)
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- A convenient, one-pot procedure for the preparation of acyl and sulfonyl fluorides using Cl3CCN, Ph3P, and TBAF(t -BuOH) 4
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Various carboxylic acids were converted into acyl fluorides in excellent yields by treatment with trichloroacetonitrile, triphenylphosphine, and TBAF(t-BuOH)4 at room temperature. The reaction was applicable to the preparation of acid-sensitive amino acid fluorides without deprotection or rearrangement
- Kim, Joong-Gon,Jang, Doo Ok
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experimental part
p. 3049 - 3052
(2011/02/25)
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- 2-Azetidinone derivatives: Design, synthesis and evaluation of cholesterol absorption inhibitors
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Fourteen new derivatives of the 2-azetidinone cholesterol absorption inhibitors have been synthesized, and three of them were enantiomerically pure. All the new compounds were evaluated for their activity to inhibit cholesterol absorption in rats, and most of them showed comparable effects in lowering the levels of total cholesterol in the serum.
- Wang, Yubin,Zhang, Huibin,Huang, Wenlong,Kong, Jing,Zhou, Jinpei,Zhang, Beibei
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experimental part
p. 1638 - 1643
(2009/05/30)
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- DNA METHYL TRANSFERASE INHIBITORS CONTAINING A ZINC BINDING MOIETY
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The present invention relates to inhibitors of DNMT containing zinc moiety derivatives that have enhanced or unique properties as inhibitors of DNA methyl transferases (DNMT) and their use in the treatment of DNMT related diseases and disorders such as cancer. The said derivatives may further act as HDAC inhibitors.
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Page/Page column 50
(2008/06/13)
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- MULTI-FUNCTIONAL SMALL MOLECULES AS ANTI-PROLIFERATIVE AGENTS
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The present invention relates to the compositions, methods, and applications of a novel approach to selective inhibition of several cellular or molecular targets with a single small molecule. More specifically, the present invention relates to multi-functional small molecules wherein one functionality is capable of inhibiting histone deacetylases (HDAC) and the other functionality is capable of inhibiting a different cellular or molecular pathway involved in aberrant cell proliferation, differentiation or survival.
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Page/Page column 228-229
(2008/06/13)
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- Structure-activity relationships of α-ketooxazole inhibitors of fatty acid amide hydrolase
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A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, K, - 2.6 nM), with 5hh (aryl -3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.
- Hardouin, Christophe,Kelso, Michael J.,Romero, F. Anthony,Rayl, Thomas J.,Leung, Donmienne,Hwang, Inkyu,Cravatt, Benjamin F.,Boger, Dale L.
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p. 3359 - 3368
(2008/02/13)
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- PREPARATION OF EZETIMIBE
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A process for preparing ezetimibe.
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Page/Page column 9
(2010/11/26)
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- SUBSTITUTED CYCLOHEXYL-1,4-DIAMINE DERIVATIVES WITH A CHAIN EXTENSION
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The invention relates to substituted cyclohexyl-1,4-diamine derivatives, to a method for their production, to medicaments containing said compounds and to the use of substituted cyclohexyl-1,4-diamine derivatives for producing medicaments.
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Page/Page column 25
(2008/06/13)
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- The chemistry of pseudomonic acid. 15. Synthesis and antibacterial activity of a series of 5-alkyl, 5-alkenyl, and 5-heterosubstituted oxazoles
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The synthesis of a range of 5-alkyl, 5-alkenyl, and 5-heterosubstituted 2- (1-normon-2-yl) oxazoles is described. The antibacterial activity was determined as the minimum inhibitory concentration against a range of Gram- positive and Gram-negative organisms using a standard Agar dilution procedure. Compounds possessing an acid functionality directly on, or close to, the ring were found to be of greatly decreased potency, while increasing lipophilicity with greater chain length led to increased potency of these derivatives.
- Brown, Pamela,Davies, David T.,O'Hanlon, Peter J.,Wilson, Jennifer M.
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p. 446 - 457
(2007/10/03)
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- Preparation and Diels-Alder Reactions of 1,1-Dicarbonylalkanes
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1,1-Dicarbonyl- (ester, ketone, lactone) substituted alkenes are prepared from the corresponding saturated 1-phenylsulfinyl derivatives.These are formed from precursor sulfides, which can be efficiently prepared either by oxidation of β-hydroxy-α-phenylsulfenylcarbonyl compounds or direct acylation of α-phenylsulfenyl enolate anions with acid chlorides.Some of the title compounds can be isolated and then reacted while others are generated and reacted in situ in a Diels-Alder fashion with cyclopentadiene.Endo-exo selectivities are discussed.
- Hoye, Thomas R.,Caruso, Andrew J.,Magee, Andrew S.
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p. 4152 - 4156
(2007/10/02)
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