Synthesis and antitumor activity of benzils related to combretastatin A-4

被引：109

作者：

Mousset, Celiine ^{[1
]}

Giraud, Anne ^{[1
]}

Provot, Olivier ^{[1
]}

Hamze, Abdallah ^{[1
]}

Bignon, Jeromr ^{[2
]}

Liu, Jian-Miao ^{[2
]}

Thoret, Sylviane ^{[2
]}

Dubois, Joelle ^{[2
]}

Brion, Jean-Daniel ^{[1
]}

Alami, Mouad ^{[1
]}

机构：

[1] Univ Paris Sud, BioCIS UMR 8076, CNRS, Lab Chim Therapeut,Fac Pharm, F-92296 Chatenay Malabry, France

[2] CNRS, Inst Chim Subst Nat, UPR 2301, F-91198 Gif Sur Yvette, France

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2008年 / 18卷 / 11期

关键词：

benzils; oxidation; alkynes; combretastatin; antitumor; antiproliferative; antimitotic; inhibition of tubulin assembly; antiangiogenic;

D O I：

10.1016/j.bmcl.2008.04.053

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of benzil derivatives related to combretastatin A-4 (CA-4) have been synthesized by oxidation of diarylalkynes promoted by PdI2 in DMSO. Using this new protocol, 14 benzils were prepared in good to excellent yields and their biological activity has been delineated. Several benzils exhibited excellent antiproliferative activity: for example, 4j and 4k bearing the greatest resemblance to CA-4 and AVE-8062, respectively, were found to inhibit cell growth at the nanomolar level (20-50 nM) on four human tumor cell lines. Flow cytometric analysis indicates that these compounds act as antimitotics and arrest the cell cycle in G(2)/M phase. A cell-based assay indicated that compounds 4j and 4k displayed a similar inhibition of tubulin assembly with an IC50 value similar to CA-4. These results clearly demonstrated that the Z-double bond of CA-4 can be replaced by a 1,2-diketone unit without significant loss of cytotoxicity and inhibition of tubulin assembly potency. (C) 2008 Elsevier Ltd. All rights reserved.

引用

页码：3266 / 3271

页数：6

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