Potent Antitumor Activities and Structure Basis of the Chiral β-Lactam Bridged Analogue of Combretastatin A-4 Binding to Tubulin

被引：83

作者：

Zhou, Pengfei ^{[1
]}

Liu, Yan ^{[2
]}

Zhou, Lu ^{[1
]}

Zhu, Kongkai ^{[2
]}

Feng, Kechang ^{[1
]}

Zhang, Hao ^{[2
]}

Liang, Yuru ^{[1
]}

Jiang, Hualiang ^{[2
]}

Luo, Cheng ^{[2
]}

Liu, Mingming ^{[1
]}

Wang, Yang ^{[1
]}

机构：

[1] Fudan Univ, Sch Pharm, Shanghai 201203, Peoples R China

[2] Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 22期

基金：

中国国家自然科学基金;

关键词：

ASYMMETRIC ALLYLIC AMINATION; BAYLIS-HILLMAN ADDUCTS; ANTICANCER AGENTS; BIOLOGICAL EVALUATION; INHIBITORS; MECHANISM; INTERACT; LIGANDS; SITE;

D O I：

10.1021/acs.jmedchem.6b01268

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of chiral,beta-lactam bridged analogues (3-substituted 1,4-diaryl-2-azetidinones) of combretastatin A-4 (CA-4) were synthesized asymmetrically, and their antitumor activities were evaluated in vitro and in vivo. The cocrystal structure of tubulin in complex with compound 9 was determined by X-ray crystallography, which showed that 9 binds to the same site as colchicine with similar binding mode, and the absolute configuration of its C-4 was first identified and demonstrated to be critically important for their antiproliferative activities.

引用

页码：10329 / 10334

页数：6

共 23 条

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