Synthesis and structure–activity relationships of pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles as potent inhibitors of tubulin polymerization

• Novel pyridinyl-1H-1,2,3-triazoles, triazolylisoxazoles, triazolyldihydroisoxazoles were designed as anti-cancer agents.
• Triazolyldihydroisoxazoles 28b and 28c shown potent anti-cancer activity and inhibited tubulin polymerization.
• FACS analysis was performed on HeLa cell lines for compounds 28b and 28c.
• Molecular modelling studies revealed that the compounds 28b and 28c binds well in the colchicine binding site of α,β-tubulin.

Three series of compounds; pyridinyl-1H-1,2,3-triazoles, pyridinyl-1H-1,2,3-triazolylisoxazoles and pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles with TMP moiety were designed, synthesized and screened for their anti-cancer and anti-tubulin properties. By sequentially designing three series of compounds comprising of dihydroisoxazole in the linker, a small substituent like chlorine on one side (R1) and aromatic group (R) on the pyridine ring, we have optimized the anti-cancer as well as anti-tubulin activity. Pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles 28b and 28c were found to be potent anti-cancer agents against all the cell lines tested with a concomitant accumulation of cells in the G2/M phase of the cell cycle. Molecular modeling suggests that the trimethoxyphenyl ring in 28b and 28c occupies the cholchicine binding domain of β-tubulin, whereas, the dihydroisoxazole extends towards the interface of α,β-tubulin.

Three series of compounds were prepared and among them, pyridinyl-1H-1,2,3-triazolyldihydroisoxazoles (28b and 28c) with TMP was found to be potent anti-cancer agents and tubulin inhibitors.Figure optionsDownload as PowerPoint slide