Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents

Yan Lu, Jianjun Chen, Jin Wang, Chien Ming Li, Sunjoo Ahn, Christina M. Barrett, James T. Dalton, Wei Li, Duane Miller

Research output: Contribution to journalArticle

37 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)7355-7366
Number of pages12
JournalJournal of Medicinal Chemistry
Volume57
Issue number17
DOIs
StatePublished - Sep 11 2014

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Tubulin Modulators
Thymidine Monophosphate
Colchicine
Liver Microsomes
Structure-Activity Relationship
Antineoplastic Agents
Binding Sites
pyridine
benzimidazole

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents. / Lu, Yan; Chen, Jianjun; Wang, Jin; Li, Chien Ming; Ahn, Sunjoo; Barrett, Christina M.; Dalton, James T.; Li, Wei; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 57, No. 17, 11.09.2014, p. 7355-7366.

Research output: Contribution to journalArticle

Lu, Yan ; Chen, Jianjun ; Wang, Jin ; Li, Chien Ming ; Ahn, Sunjoo ; Barrett, Christina M. ; Dalton, James T. ; Li, Wei ; Miller, Duane. / Design, synthesis, and biological evaluation of stable colchicine binding site tubulin inhibitors as potential anticancer agents. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 17. pp. 7355-7366.
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