Docking, Synthesis and Antiproliferative Activity of N-Acylhydrazone Derivatives Designed as Combretastatin A4 Analogues

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Citações na Scopus
56
Tipo de produção
article
Data de publicação
2014
Título da Revista
ISSN da Revista
Título do Volume
Editora
PUBLIC LIBRARY SCIENCE
Autores
AMARAL, Daniel Nascimento do
CAVALCANTI, Bruno C.
BEZERRA, Daniel P.
FERREIRA, Paulo Michel P.
CASTRO, Rosane de Paula
SABINO, Jose Ricardo
PESSOA, Claudia
SANT'ANNA, Carlos M. R.
Citação
PLOS ONE, v.9, n.3, article ID e85380, 16p, 2014
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Cancer is the second most common cause of death in the USA. Among the known classes of anticancer agents, the microtubule-targeted antimitotic drugs are considered to be one of the most important. They are usually classified into microtubule-destabilizing (e. g., Vinca alkaloids) and microtubule-stabilizing (e. g., paclitaxel) agents. Combretastatin A4 (CA-4), which is a natural stilbene isolated from Combretum caffrum, is a microtubule-destabilizing agent that binds to the colchicine domain on beta-tubulin and exhibits a lower toxicity profile than paclitaxel or the Vinca alkaloids. In this paper, we describe the docking study, synthesis, antiproliferative activity and selectivity index of the N-acylhydrazone derivatives (5a-r) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of beta-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values <= 18 mu M and >= 4 nM) were identified. Among these active compounds, LASSBio-1586 (5b) emerged as a simple antitumor drug candidate, which is capable of inhibiting microtubule polymerization and possesses a broad in vitro and in vivo antiproliferative profile, as well as a better selectivity index than the prototype CA-4, indicating improved selective cytotoxicity toward cancer cells.
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