title: Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Tennessee , Health Science Center, Memphis, Tennessee 38163, United States.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Jianjun
authors.initials: J
authors.lastname: Chen
authors.forename: Jin
authors.initials: J
authors.lastname: Wang
authors.forename: Chien-Ming
authors.initials: CM
authors.lastname: Li
authors.forename: Sunjoo
authors.initials: S
authors.lastname: Ahn
authors.forename: Christina M
authors.initials: CM
authors.lastname: Barrett
authors.forename: James T
authors.initials: JT
authors.lastname: Dalton
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Duane D
authors.initials: DD
authors.lastname: Miller
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003078:Colchicine / Q000737:chemistry* / Q000378:metabolism; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D050257:Tubulin Modulators; D003078:Colchicine