Design, synthesis and biological evaluation of a novel tubulin inhibitor 7a3 targeting the colchicine binding site

Based on the anti-proliferative activities, a novel tubulin inhibitor 7a3 targeting the colchicine binding site was designed, synthesized, and optimized from a series of novel cis-restricted pyrazole analogues of combretastatin A-4. The targeting identification of 7a3 was illuminated by solving the crystal structure of 7a3 in complex with tubulin at a resolution of 3.2 Å (PDB code 5Z4U). Moreover, the anti-tumour activity and pharmacokinetic analysis in vivo were performed to demonstrate that 7a3 is a potential microtubule-targeting drug for cancer therapy.382