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

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• 作者：Cé ; line Mousset ; Anne Giraud ; Olivier Provot ; Abdallah Hamze ; Jé ; rô ; me Bignon ; Jian-Miao Liu ; Sylviane Thoret ; Joë ; lle Dubois ; Jean-Daniel Brion ; Mouâ ; d Alami
• 关键词：Benzils ; Oxidation ; Alkynes ; Combretastatin ; Antitumor ; Antiproliferative ; Antimitotic ; Inhibition of tubulin assembly ; Antiangiogenic
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：1 June 2008
• 卷：18
• 期：11
• 页码：3266-3271
• 文件大小：345 K

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 G₂/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.