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Title: | Docking, Synthesis and Antiproliferative Activity of N-Acylhydrazone Derivatives Designed as Combretastatin A4 Analogues |
Authors: | AMARAL, Daniel Nascimento do; CAVALCANTI, Bruno C.; BEZERRA, Daniel P.; FERREIRA, Paulo Michel P.; CASTRO, Rosane de Paula; SABINO, Jose Ricardo; MACHADO, Camila Maria Longo; CHAMMAS, Roger; PESSOA, Claudia; SANT'ANNA, Carlos M. R.; BARREIRO, Eliezer J.; LIMA, Lidia Moreira |
Citation: | PLOS ONE, v.9, n.3, article ID e85380, 16p, 2014 |
Abstract: | 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. |
Appears in Collections: | Artigos e Materiais de Revistas Científicas - FM/MDR Artigos e Materiais de Revistas Científicas - LIM/24 Artigos e Materiais de Revistas Científicas - LIM/43 Artigos e Materiais de Revistas Científicas - ODS/03 |
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art_AMARAL_Docking_Synthesis_and_Antiproliferative_Activity_of_N_Acylhydrazone_2014.PDF | publishedVersion (English) | 6.93 MB | Adobe PDF | View/Open |
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