PLoS ONE (Jan 2014)

Docking, synthesis and antiproliferative activity of N-acylhydrazone derivatives designed as combretastatin A4 analogues.

  • Daniel Nascimento do Amaral,
  • Bruno C Cavalcanti,
  • Daniel P Bezerra,
  • Paulo Michel P Ferreira,
  • Rosane de Paula Castro,
  • José Ricardo Sabino,
  • Camila Maria Longo Machado,
  • Roger Chammas,
  • Claudia Pessoa,
  • Carlos M R Sant'Anna,
  • Eliezer J Barreiro,
  • Lídia Moreira Lima

DOI
https://doi.org/10.1371/journal.pone.0085380
Journal volume & issue
Vol. 9, no. 3
p. e85380

Abstract

Read online

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 β-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 β-tubulin were recognized, and several compounds with moderate to high antiproliferative potency (IC50 values ≤18 µM 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.