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Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities

文献类型：期刊论文

作者Liu, Zulong1; Zhou, Zuyu1; Tian, Wei2; Fan, Xing1; Xue, Ding1; Yu, Long3; Yu, Qiang1; Long, Ya-Qiu1
刊名CHEMMEDCHEM
出版日期2012-04
卷号7期号:4页码:680-693
关键词antitumor agents benzenesulfonamidoacetamides bioactive compounds screening tubulin
ISSN号1860-7179
DOI10.1002/cmdc.201100529
文献子类Article
英文摘要The discovery and optimization of a series of 2-N-aryl-substituted benzenesulfonamidoacetamides as novel tubulin polymerization inhibitors are described. Pharmacophore exploration of hit compound AH-487 identified the optimal structure of N-heteroaryl-2-(4-methoxy-N-(3-(trifluoromethyl)phenyl)phenylsulfonamido)acetamide as a potent antimitotic agent. Subsequent lead compounds 4?b and 4?c, with N-4-aminophenyl and N-1H-indol-5-yl substitutions at the acetamide position, respectively, were shown to induce cell-cycle arrest at the G2/M phase and lead to an accumulation of HeLa cells in the sub-G1 phase. More significantly, these lead compounds (3?c, 4?b, and 4?c) exhibit impressive cytotoxicity against a panel of cancer cells including P-glycoprotein-overexpressing MDR-positive cells, with potency greater than or equal to clinically studied benzenesulfonamide E7010. Mechanistic studies demonstrated that derivatives of AH-487 disrupt mitotic spindles by inhibiting microtubule polymerization and induce apoptosis via induction of Bcl-2 phosphorylation in tumor cells. The optimized leads 4?b and 4?c strongly inhibited the growth of human hepatocellular carcinoma cells in a mouse xenograft model.
WOS关键词CELL-CYCLE INHIBITOR ; HUMAN CANCER-CELLS ; PHASE-I ; MICROTUBULE DYNAMICS ; ACTIVE METABOLITE ; SULFONAMIDE AGENT ; ANTICANCER AGENT ; FLOW-CYTOMETRY ; SOLID TUMORS ; E7070
资助项目National Natural Science Foundation of China[81021062] ; National Natural Science Foundation of China[31129004] ; National Natural Science Foundation of China[31000619] ; National Natural Science Foundation of China[81102848] ; Shanghai Science and Technology Research Grant[08DZ1971403]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000302073100016
出版者WILEY-V C H VERLAG GMBH
源URL[http://119.78.100.183/handle/2S10ELR8/278134]  
专题药理学第一研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
药物化学研究室
通讯作者Liu, Zulong
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Peoples R China;
3.Fudan Univ, State Key Lab Genet Engn, Inst Genet, Sch Life Sci, Shanghai 200433, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Zulong,Zhou, Zuyu,Tian, Wei,et al. Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities[J]. CHEMMEDCHEM,2012,7(4):680-693.
APA Liu, Zulong.,Zhou, Zuyu.,Tian, Wei.,Fan, Xing.,Xue, Ding.,...&Long, Ya-Qiu.(2012).Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities.CHEMMEDCHEM,7(4),680-693.
MLA Liu, Zulong,et al."Discovery of Novel 2-N-Aryl-Substituted Benzenesulfonamidoacetamides: Orally Bioavailable Tubulin Polymerization Inhibitors with Marked Antitumor Activities".CHEMMEDCHEM 7.4(2012):680-693.

入库方式： OAI收割

来源：上海药物研究所

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