Drug-Clinical Agent Molecular Hybrid: Synthesis ofDiaryl(trifluoromethyl)pyrazoles as Tubulin Targeting Anticancer Agents

摘要

Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional N-heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin-(trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3-(trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 (>C-23) was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, >C-23 displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. >C-23 depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. >C-23 inhibited the assembly of tubulin in vitro. >C-23 bound to tubulin at the colchicine binding site and altered the secondary structuresof tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazoleas a cis-restricted double bond-alternative bridging motif, and carboxymethyl-substitutedphenyl as ring B for activities and interaction with tubulin. Theresults indicated that the combretastatin-(trifluoromethyl)pyrazolehybrid class of analogues has the potential for further developmentas anticancer agents.