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European journal of medicinal chemistry 163건

  1. [해외논문]   Editorial board  


    European journal of medicinal chemistry v.143 ,pp. IFC , 2018 , 0223-5234 ,

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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  2. [해외논문]   Graphical contents list   SCI SCIE


    European journal of medicinal chemistry v.143 ,pp. iii - xliii , 2018 , 0223-5234 ,

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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  3. [해외논문]   Editorial board   SCI SCIE


    European journal of medicinal chemistry v.143 ,pp. IFC - IFC , 2018 , 0223-5234 ,

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    회원님의 원문열람 권한에 따라 열람이 불가능 할 수 있으며 권한이 없는 경우 해당 사이트의 정책에 따라 회원가입 및 유료구매가 필요할 수 있습니다.이동하는 사이트에서의 모든 정보이용은 NDSL과 무관합니다.

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  4. [해외논문]   Photoresponsive azo-combretastatin A-4 analogues   SCI SCIE

    Rastogi, Shiva K. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Zhao, Zhenze (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Barrett, Scott L. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Shelton, Spencer D. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Zafferani, Martina (Department of Chemistry, Albion College, 611 E. Porter Str., Albion, MI 49224, USA ) , Anderson, Hailee E. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Blumenthal, Madeleine O. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Jones, Lindsey R. (Department of Chemistry and Biochemistry, 601 University Drive, Texas State University, San Marcos, TX 78666, USA ) , Wang, Lei (Chemistry Department, University of South Florida, Tampa, FL 33620, USA ) , Li, Xiaopeng (Chemistry Department, Univers) , Streu, Craig N. , Du, Liqin , Brittain, William J.
    European journal of medicinal chemistry v.143 ,pp. 1 - 7 , 2018 , 0223-5234 ,

    초록

    Abstract Colchicine analogues in which an azo group is incorporated into a molecule containing the key pharmacophore of colchicine, have found particular utility as switchable tubulin binding chemotherapeutics. Combretastatin is a related compound containing a stilbene fragment that shows different bioactivity for the cis and trans isomers. We have performed cell assays on 17 new compounds structurally related to a previously reported azo-analogue of combretastatin. One of these compounds showed enhanced potency against HeLa (IC 50 = 0.11 μM) and H157 cells (IC 50 = 0.20 μM) for cell studies under 400 nm irradiation and the highest photoactivity (IC 50 with irradiation/IC 50 in dark = 550). We have performed docking and physicochemical studies of this new compound ( 7 ). Kinetic studies in water reveal a longer half-life for the cis isomer of 7 which may be one factor responsible for the better IC 50 values in cell assays and the improved photoresponsive behavior. Highlights Seventeen analogues of azocombretastatin A-4 were tested for photopharmacological activity against HeLa and H157 cell lines. Compound 7 displayed ∼2× improved activity relative to previously reported A-4 (compound 5 ). The structural difference between 7 and 5 is an ethoxy substitution for methoxy on the A-ring. The hypothesis to account for this improved activity is based on differential aqueous solubility of cis and trans isomers. Graphical abstract [DISPLAY OMISSION]

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  5. [해외논문]   Synthesis and biological evaluation of N-substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid derivatives as tubulin polymerization inhibitors   SCI SCIE

    Qi, Jianguo (Corresponding author. ) , Dong, Haiyang (Corresponding author.) , Huang, Jing , Zhang, Shufeng , Niu, Linqiang , Zhang, Yahong , Wang, Jianhong
    European journal of medicinal chemistry v.143 ,pp. 8 - 20 , 2018 , 0223-5234 ,

    초록

    Abstract A series of novel N -substituted 3-oxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxy- lic acid derivatives were synthesized and evaluated for their biological activities. Among all synthesized target compounds, 13d exhibited the most potent antiproliferative activity against HeLa, SMMC-7721, K562 cell line (IC 50 = 0.126 μM, 0.071 μM, 0.164 μM, respectively). Furthermore, compound 13d inhibited tubulin polymerization (IC 50 = 3.97 μM), arrested cell cycle at the G2/M phase and induced apoptosis. The binding mode at the colchicine binding site was also probed. These studies provided a new molecular scaffold for the further development of antitumor agents that target tubulin. Highlights A series of novel quinoxalinone analogues were synthesized. The antiproliferative activities against three cancer cell lines were determined. The lead compound 13d showed IC 50 values up to nanomolar level. 13d inhibited tubulin polymerization, induced cell cycle arrest and apoptosis. The binding site and binding mode of 13d were probed. Graphical abstract [DISPLAY OMISSION]

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  6. [해외논문]   Synthesis of unprecedented steroidal spiro heterocycles as potential antiproliferative drugs   SCI SCIE

    Romero-Herná (Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico ) , ndez, Laura L. (Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico ) , Merino-Montiel, Pené (Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico ) , lope (Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, 72570 Puebla, Pue., Mexico ) , Meza-Reyes, Socorro (Departamento de Química Orgánica, Facultad de Química, Universidad de Sevilla, Apartado 1203, E-41071 Seville, Spain ) , Vega-Baez, José (BioLab, Instituto Universitario de Bio-Orgánica “Antonio González” (IUBO-AG), Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Universidad de La Laguna, c/ Astrofísico Francisco Sánchez 2, 38206 La Laguna, Spain ) , Luis (Facultad de) , Ló , pez, Ó , scar , Padró , n, José , M. , Montiel-Smith, Sara
    European journal of medicinal chemistry v.143 ,pp. 21 - 32 , 2018 , 0223-5234 ,

    초록

    Abstract Herein we report the straightforward preparation of novel conformationally-restricted steroids from trans -androsterone and estrone, decorated with spiranic oxazolidin-2-one or 2-aminooxazoline motifs at C-17 as potential antiproliferative agents. Such unprecedented pharmacophores were accessed using an aminomethylalcohol derivative at C-17 as the key intermediate; reaction of such functionality with triphosgene, or conversion into N-substituted thioureas, followed by an intramolecular cyclodesulfurization reaction promoted by yellow HgO, furnished such spirocycles in excellent yields. Title compounds were tested in vitro against a panel of six human tumor cell lines, named A549 (non-small cell lung), HBL-100 (breast), HeLa (cervix), SW1573 (non-small cell lung), T-47D (breast) and WiDr (colon), and the results were compared with steroidal chemotherapeutic agents (abiraterone and galeterone); the A-ring of the steroidal backbone, the nature of the heterocycle and the N-substituents proved to be essential motifs for establishing structure-activity relationships concerning not only the potency but also the selectivity against tumor cell lines. Estrone derivatives, particularly those bearing a spiranic 2-aminooxazoline scaffold were found to be the most active compounds, with GI 50 values ranging from the low micromolar to the submicromolar level (0.34–1.5 μM). Noteworthy, the lead compounds showed a remarkable increase in activity against the resistant cancer cell lines (T-47D and WiDr) compared to the anticancer reference drugs (up to 120-fold). Highlights Stereoselective synthesis of conformationally-restricted spiranic heterocycles from trans -androsterone and estrone. Treatment of aminomethyl alcohol at C-17 with triphosgene furnishes spiranic oxazolin-2-ones. Cyclodesulfurization reaction of hydroxyl thioureas at C-17 furnishes spiranic 2-aminooxazolines. Observed order of activity: aminooxazoline > spirocarbamate > thiourea. Spiro-heterocycles from estrone are the lead antiproliferative agents (0.34–1.5 μM). Graphical abstract [DISPLAY OMISSION]

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  7. [해외논문]   Discovery of novel propargylamine-modified 4-aminoalkyl imidazole substituted pyrimidinylthiourea derivatives as multifunctional agents for the treatment of Alzheimer's disease   SCI SCIE

    Xu, Yi-xiang (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China ) , Wang, Huan (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ) , Li, Xiao-kang (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China ) , Dong, Sheng-nan (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ) , Liu, Wen-wen (Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Mei Long Road, Shanghai 200237, China ) , Gong, Qi (CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ) , Wang, Tian-duan-yi (Shanghai Key Laboratory of New Drug Design, School of Pharmac) , Tang, Yun , Zhu, Jin , Li, Jian , Zhang, Hai-yan , Mao, Fei
    European journal of medicinal chemistry v.143 ,pp. 33 - 47 , 2018 , 0223-5234 ,

    초록

    Abstract A series of novel propargylamine-modified pyrimidinylthiourea derivatives ( 1–3 ) were designed and synthesized as multifunctional agents for Alzheimer's disease (AD) therapy, and their potential was evaluated through various biological experiments. Among these derivatives, compound 1b displayed good selective inhibitory activity against AChE ( vs BuChE, IC 50 = 0.324 μM, SI > 123) and MAO-B ( vs MAO-A, IC 50 = 1.427 μM, SI > 35). Molecular docking study showed that the pyrimidinylthiourea moiety of 1b could bind to the catalytic active site (CAS) of AChE, and the propargylamine moiety interacted directly with the flavin adenine dinucleotide (FAD) of MAO-B. Moreover, 1b demonstrated mild antioxidant ability, good copper chelating property, effective inhibitory activity against Cu 2+ -induced A β 1−42 aggregation, moderate neuroprotection, low cytotoxicity, and appropriate blood−brain barrier (BBB) permeability in vitro and was capable of ameliorating scopolamine-induced cognitive impairment in mice. These results indicated that 1b has the potential to be a multifunctional candidate for the treatment of Alzheimer's disease. Highlights Novel compounds with good multifunctional anti-AD activities were discovered. Compound 1b showed potential druggability: low cytotoxicity and BBB permeability. Compound 1b ameliorated scopolamine-induced cognitive impairment in mice. Graphical abstract [DISPLAY OMISSION]

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  8. [해외논문]   Discovery and structure-activity relationship of novel 4-hydroxy-thiazolidine-2-thione derivatives as tumor cell specific pyruvate kinase M2 activators   SCI SCIE

    Li, Ridong (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Ning, Xianling (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Zhou, Shuo (Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentuchy, 789 South Lime-stone Street, Lexington, KY 40536, USA ) , Lin, Zhiqiang (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Wu, Xingyu (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Chen, Hong (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Bai, Xinyu (Institute of Systems Biomedicine, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, PR China ) , Wang, Xin (State Key Laboratory of Natural and Biomimet) , Ge, Zemei , Li, Runtao , Yin, Yuxin
    European journal of medicinal chemistry v.143 ,pp. 48 - 65 , 2018 , 0223-5234 ,

    초록

    Abstract Pyruvate kinase M2 isoform (PKM2) is a crucial protein responsible for aerobic glycolysis of cancer cells. Activation of PKM2 may alter aberrant metabolism in cancer cells. In this study, we discovered a 4-hydroxy-thiazolidine-2-thione compound 2 as a novel PKM2 activator from a random screening of an in-house compound library. Then a series of novel 4-hydroxy-thiazolidine-2-thione derivatives were designed and synthesized for screening as potent PKM2 activators. Among these, some compounds showed higher PKM2 activation activity than lead compound 2 and also exhibited significant anti-proliferative activities on human cancer cell lines at nanomolar concentration. The compound 5w was identified as the most potent antitumor agent, which showed excellent anti-proliferative effects with IC 50 values from 0.46 μM to 0.81 μM against H1299, HCT116, Hela and PC3 cell lines. 5w also showed less cytotoxicity in non-tumor cell line HELF compared with cancer cells. In addition, Preliminary pharmacological studies revealed that 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. The best PKM2 activation by compound 5t was rationalized through docking studies. Highlights Discovery of 4-hydroxy-thiazolidine-2-thione derivatives as PKM2 activators. Most compounds showed significant antiproliferative activities. Compound 5w exhibited potent activities against four types of tumor cells at nanomolar concentration. Compound 5w arrests the cell cycle at the G2/M phase in HCT116 cell line. Graphical abstract [DISPLAY OMISSION]

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  9. [해외논문]   Novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents: Design, synthesis and biological evaluation   SCI SCIE

    Liu, Han-Bo (Corresponding author. ) , Gao, Wei-Wei (Corresponding author.) , Tangadanchu, Vijai Kumar Reddy , Zhou, Cheng-He , Geng, Rong-Xia
    European journal of medicinal chemistry v.143 ,pp. 66 - 84 , 2018 , 0223-5234 ,

    초록

    Abstract A series of novel aminopyrimidinyl benzimidazoles as potentially antimicrobial agents were designed, synthesized and characterized by IR, NMR and HRMS spectra. The biological evaluation in vitro revealed that some of the target compounds exerted good antibacterial and antifungal activity in comparison with the reference drugs. Noticeably, compound 7d could effectively inhibit the growth of A. flavus , E. coli DH52 and MRSA with MIC values of 1, 1 and 8 μg/mL, respectively. Further studies revealed that pyrimidine derivative 7d could exhibit bactericidal mode of action against both Gram positive ( S. aureus and MRSA) and Gram negative ( P. aeruginosa ) bacteria. The active molecule 7d showed low cell toxicity and did not obviously trigger the development of resistance in bacteria even after 16 passages. Furthermore, compound 7d was able to beneficially regulate reactive oxygen species (ROS) generation for an excellent safety profile. Molecular docking study revealed that compound 7d could bind with DNA gyrase by the formation of hydrogen bonds. The preliminary exploration for antimicrobial mechanism disclosed that compound 7d could effectively intercalate into calf thymus DNA to form a steady supramolecular complex, which might further block DNA replication to exert the powerful bioactivities. The binding investigation of compound 7d with human serum albumins (HSA) revealed that this molecule could be effectively transported by HSA. Highlights Novel aminopyrimidinyl benzimidazoles with good antimicrobial potency were developed. Compound 7d showed broad spectrum and beneficial regulation for ROS generation. Compound 7d with low toxicity did not trigger the resistance development in bacteria. MEPs and molecular docking rationalized the antimicrobial activity. Compound 7d could intercalate into DNA and be effectively stored and carried by HSA. Graphical abstract A series of novel aminopyrimidinyl benzimidazoles were synthesized and screened for their antimicrobial activities. Molecular modeling and experimental investigation with DNA suggested the possible antibacterial mechanism. [DISPLAY OMISSION]

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  10. [해외논문]   Design, synthesis and pharmacological evaluation of N-(5-chloro-2,4-dihydroxybenzoyl)-(R)-N-arylmethyl-1,2,3,4-tetrahydro-3-isoquinolinecarboxamides as potent Hsp90 inhibitors   SCI SCIE

    Liang, Chuanpeng (Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China ) , Wu, Xingkang (Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China ) , Li, Zhenyu (Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, 250021 PR China ) , Zhu, Jing (State Key Laboratory of Microbial Technology, Shandong University, Jinan, Shandong 250100, PR China ) , Lu, Chunhua (Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China ) , Shen, Yuemao (Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong 250012, PR China)
    European journal of medicinal chemistry v.143 ,pp. 85 - 96 , 2018 , 0223-5234 ,

    초록

    Abstract Using diverse arylmethyl groups to replace the benzyl moiety of the lead Hsp90 inhibitor 1 ( N -(5-chloro-2,4-dihydroxybenzoyl)-( R )- N -benzyl-1,2,3,4-tetrahydro-3-iso quinolinecarboxamide), thirty four derivatives ( 10 – 43 ) were developed, and exhibited improved Hsp90 inhibitory and antiproliferative activities. SAR analysis indicated that the southeastern aryl substitutions influenced their antiproliferative activities obviously, with the para -pyridyl group ( 41 ) outperforming all other substitution patterns. In this regard, compound 41 was selected for further evaluation. CETSA melt and ITDRF CETSA (isothermal dose-response fingerprint) curves for Hsp90α further proved that 41 interacted with intracellular Hsp90α powerfully. Compared with the lead compound 1 , docking and MD refinement of the Hsp90α- 41 complex revealed a favorable H-bonding interaction between the side-chain of Tyr139 and the pyridine moiety of 41 , which is the first time to be used for resorcinol-based Hsp90 inhibitors. With broad-spectral antitumor activity, compound 41 induced time- and dose-dependent growth inhibition and G0/G1 cell cycle arrest on human breast cancer MDA-MB-453 cell line. In addition, flow cytometry and Western blot analyses confirmed that 41 induced apoptosis of human breast cancer MDA-MB-453 cell line. Via degradation of IKKs and suppression of IKKs activity, compound 41 inhibited TNF-α-induced NF-κB activation. The overall properties warrant compound 41 a promising Hsp90 inhibitor and further biological characterizations. This study provides insights into the chemical evolution of Hsp90 inhibitors, and may facilitate the design of next generation Hsp90 inhibitors for the antitumor drug development. Highlights A structure-based optimization was conducted on the lead Hsp90 inhibitor 1. CETSA and WB showed that 41 with the para -pyridyl group bound to cellular Hsp90α. Compound 41 formed an H-bonding interaction with the side-chain of Tyr139. Compound 41 inhibited tumor cells growth, induces cell cycle arrest and apoptosis. Compound 41 inhibited TNF-α-induced NF-κB activation through IKKs. Graphical abstract [DISPLAY OMISSION]

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