%0 Journal Article
%T Docking, Synthesis and Antiproliferative Activity of N-Acylhydrazone Derivatives Designed as Combretastatin A4 Analogues
%A Daniel Nascimento do Amaral
%A Bruno C. Cavalcanti
%A Daniel P. Bezerra
%A Paulo Michel P. Ferreira
%A Rosane de Paula Castro
%A Jos¨¦ Ricardo Sabino
%A Camila Maria Longo Machado
%A Roger Chammas
%A Claudia Pessoa
%A Carlos M. R. Sant'Anna
%A Eliezer J. Barreiro
%A L¨ªdia Moreira Lima
%J PLOS ONE
%D 2014
%I Public Library of Science (PLoS)
%R 10.1371/journal.pone.0085380
%X 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 ¦Â-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¨Cr) designed as CA-4 analogues. The essential structural requirements for molecular recognition by the colchicine binding site of ¦Â-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ¡Ü18 ¦ÌM and ¡Ý4 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.
%U http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0085380