Chemistry & Biology 2005-09-01

Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.

Yali Kong, Jolanta Grembecka, Michael C Edler, Ernest Hamel, Susan L Mooberry, Michal Sabat, Jayson Rieger, Milton L Brown

文献索引：Chem. Biol. 12(9) , 1007-14, (2005)

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摘要

Targeting the microtubule system represents an attractive strategy for the development of anticancer agents. In this study, we report a class of combretastatin A-4 (CA-4) analogs derivatized with a boronic acid moiety replacing the hydroxyl group on the C-ring of CA-4. Docking studies of the X-ray structures of our aryl-boronic analogs onto an X-ray structure of the alpha,beta-tubulin heterodimer suggested that cis-6 was a potent inhibitor of the colchicine binding. The model indicated that there would be strong hydrogen bonding between the boronic acid moiety and Thr-179 and Val-181 of alpha-tubulin. We demonstrate that the cis-6 boronic acid bioisostere of CA-4: (1) inhibits tubulin assembly, (2) competitively displaces colchicine, and (3) is a low-nanomolar inhibitor of human cancer cell lines. We present this isostere as a class of potent analogs of CA-4.

相关化合物

  • 3-溴-4-甲氧基苯甲...

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