Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents
Lu, Y.; Chen, J.; Wang, J.; Li, C.-M.; Ahn, S.; Barrett, C.M.; Dalton, J.T.; Li, W.; Miller, D.D.
Journal of Medicinal Chemistry 57(17): 7355-7366
ISSN/ISBN: 1520-4804 PMID: 25122533 DOI: 10.1021/jm500764v
To block the metabolically labile sites of novel tubulin inhibitors targeting the colchicine binding site based on SMART, ABI, and PAT templates, we have designed, synthesized, and biologically tested three focused sets of new derivatives with modifications at the carbonyl linker, the para-position in the C ring of SMART template, and modification of A ring of the PAT template. Structure-activity relationships of these compounds led to the identification of new benzimidazole and imidazo[4,5-c]pyridine-fused ring templates, represented by compounds 4 and 7, respectively, which showed enhanced antitumor activity and substantially improved the metabolic stability in liver microsomes compared to SMART. MOM group replaced TMP C ring and generated a potent analogue 15, which showed comparable potency to the parent SMART compound. Further modification of PAT template yielded another potent analogue 33 with 5-indolyl substituent at A ring.