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

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 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.

• Authors: 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
• Journal: PloS one (PLoS One) Vol. 9 Issue 3 Pg. e85380 ( 2014) ISSN: 1932-6203 [Electronic] United States
• PMID: 24614859 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydrazones
• Stilbenes
• Tubulin
• fosbretabulin
• Colchicine
• Fluorouracil

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Binding Sites
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Colchicine (pharmacology)
• Drug Design
• Female
• Fluorouracil (pharmacology)
• Humans
• Hydrazones (chemistry, pharmacology)
• Hydrogen Bonding
• Inhibitory Concentration 50
• Mice, Inbred BALB C
• Mice, Nude
• Microtubules (metabolism)
• Molecular Docking Simulation
• Stilbenes (chemistry, pharmacology)
• Tubulin (metabolism)