Highly potent triazole-based tubulin polymerization inhibitors

Abstract

We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors that contain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond in combretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerization inhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant (MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, as exemplified by compound 7, conferred optimal properties among this series. Computer docking and molecular simulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likely to interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It is hoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles as potential anti-cancer therapeutic agents.

Figure 1

Known SAR of CA-4 analogues.

Chart 1

Scheme 1a

Scheme 2a

Figure 2

X-ray crystal structure of compound 7. Atoms are depicted as 50% thermal probability ellipsoids.

Figure 3

Binding conformation of compound 7 docked inside colchicine binding site of tubulin: perspective view (upper panel) and close-up view (lower panel) of bound ligand inside tubulin binding site. Compound 7 is rendered in ball-and-stick mode and colored by atom type. In the upper panel, tubulin is displayed as a flat ribbon with α-tubulin colored green and β-tubulin colored magenta. Residues Ala α180, Val α181, and Cys β239 are displayed in stick mode. In the lower panel, the residues interacting with the ligand are rendered in stick mode and labeled. Hydrogen bonds are depicted as green dotted lines. The triazole N2 atom is labeled accordingly.