Combretastatin-like chalcones as inhibitors of microtubule polymerization. Part 1: Synthesis and biological evaluation of antivascular activity

被引：212

作者：

Ducki, Sylvie ^{[1
,2
,3
,4
]}

Rennison, David ^{[1
,2
]}

Woo, Meiko ^{[1
,2
]}

Kendall, Alexander ^{[1
,2
]}

Chabert, Jeremie Fournier Dit ^{[3
,4
]}

McGown, Alan T. ^{[2
,3
]}

Lawrence, Nicholas J. ^{[1
,5
]}

机构：

[1] Univ Manchester, Dept Chem, Manchester M60 1QD, Lancs, England

[2] Christie Hosp NHS Trust, Paterson Inst Canc Res, CRC Drug Dev Grp, Manchester M20 4BX, Lancs, England

[3] Univ Salford, Ctr Mol Drug Design, Salford M5 4WT, Lancs, England

[4] Clermont Univ, ENSCCF, EA987, Lab Chim Heterocyles & Glucides, F-63174 Aubiere, France

[5] Univ S Florida, Dept Interdisciplinary Oncol, H Lee Moffitt Canc Ctr & Res Inst, Drug Discovery Program, Tampa, FL 33612 USA

来源：

BIOORGANIC & MEDICINAL CHEMISTRY | 2009年 / 17卷 / 22期

基金：

英国工程与自然科学研究理事会;

关键词：

Chalcone; Combretastatin; Tubulin; Antivascular; Anticancer; Colchicine; SD400; CELL-GROWTH; ANTINEOPLASTIC AGENTS; CRYSTAL-STRUCTURE; TUBULIN; ANALOGS; A-4; COLCHICINE; PHOSPHATE; NUCLEATION; POTENT;

D O I：

10.1016/j.bmc.2009.09.039

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

The alpha-methyl chalcone SD400 is a potent inhibitor of tubulin assembly and possesses potent anticancer activity. Various chalcone analogues were synthesized and evaluated for their cell growth inhibitory properties against the K562 human chronic myelogenous leukemia cell line (SD400, IC50 0.21 nM; combretastatin A4 CA4, IC50 2.0 nM). Cell cycle analysis by flow cytometry indicated that these agents are antimitotic (SD400, 83% of the cells are in G(2)/M phase; CA4 90%). They inhibit tubulin assembly at low concentration (SD400, IC50 0.46 mu M; CA4, 0.10 mu M) and compete with [H-3] colchicine for binding to tubulin (8% [H-3] colchicine remained bound to tubulin after competition with SD400 or CA4). Upon treatment with SD400, remarkable cell shape changes were elicited in HUVEC cells, consistent with vasculature damaging activity. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：7698 / 7710

页数：13

共 53 条

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SYNTHESIS OF (+/-)-DEOXYSCHIZANDRIN [J].