Design, synthesis and biological evaluation of colchicine glycoconjugates as tubulin polymerization inhibitors

A series of new colchicine glycoconjugates as tubulin polymerization inhibitors were designed by targeting strategy based on Warburg effect. All of the colchicine glycoconjugates were synthesized and then evaluated for their antiproliferative activities against three human cancer lines HT-29, MCF-7 and Hep-3B. Among them, 1e exhibited greater than 10 times selectivity between GLUT1 highly expressed cells (HT-29 and MCF-7) and GLUT1 lowly expressed cells (Hep-3B), and also showed lower cytotoxicity against HUVECs compared with colchicine. Moreover, 1e significantly inhibited tubulin polymerization and disrupted microtubule networks. GLUT1 inhibitor-dependent cytotoxicity assay demonstrated that the uptake of 1e was regulated via GLUT1. Molecular docking studies showed that 1e could be a substrate of GLUT1 and bind to the colchicine site of tubulin.

Automated summary

A series of new colchicine glycoconjugates were designed as tubulin polymerization inhibitors and their antiproliferative activities were evaluated. Among them, compound 1e exhibited excellent selectivity and low cytotoxicity. Moreover, it significantly inhibited tubulin polymerization and disrupted microtubule networks.