Design, Synthesis, and Biological Evaluation of Stable Colchicine-Binding Site Tubulin Inhibitors 6‑Aryl-2-benzoyl-pyridines as Potential Anticancer Agents

We
previously reported a potent tubulin inhibitor CH-2-77. In this
study, we optimized the structure of CH-2-77 by blocking metabolically
labile sites and synthesized a series of CH-2-77 analogues. Two compounds, 40a and 60c, preserved the potency while improving
the metabolic stability over CH-2-77 by 3- to 4-fold (46.8 and 29.4
vs 10.8 min in human microsomes). We determined the high-resolution
X-ray crystal structures of 40a (resolution 2.3 Å)
and 60c (resolution 2.6 Å) in complex with tubulin
and confirmed their direct binding at the colchicine-binding site. In vitro, 60c maintained its mode of action
by inhibiting tubulin polymerization and was effective against P-glycoprotein-mediated
multiple drug resistance and taxol resistance. In vivo, 60c exhibited a strong inhibitory effect on tumor
growth and metastasis in a taxol-resistant A375/TxR xenograft model
without obvious toxicity. Collectively, this work showed that 60c is a promising lead compound for further development as
a potential anticancer agent.