Structure-based discovery of a boronic acid bioisostere of combretastatin A-4.
Chem Biol
; 12(9): 1007-14, 2005 Sep.
Article
em En
| MEDLINE
| ID: mdl-16183025
ABSTRACT
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.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Estilbenos
/
Ácidos Borônicos
/
Antineoplásicos Fitogênicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2005
Tipo de documento:
Article