Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents

Yan Lu, Chien Ming Li, Zhao Wang, Jianjun Chen, Michael L. Mohler, Wei Li, James T. Dalton, Duane Miller

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

In a continued effort to improve upon the previously published 4-substituted methoxybenzoyl-aryl-thiazole (SMART) template, we explored chemodiverse "B" rings and "B" to "C" ring linkage. Further, to overcome the poor aqueous solubility of this series of agents, we introduced polar and ionizable hydrophilic groups to obtain water-soluble compounds. For instance, based on in vivo pharmacokinetic (PK) studies, an orally bioavailable phenyl-amino-thiazole (PAT) template was designed and synthesized in which an amino linkage was inserted between "A" and "B" rings of compound 1. The PAT template maintained nanomolar (nM) range potency against cancer cell lines via inhibiting tubulin polymerization and was not susceptible to P-glycoprotein mediated multidrug resistance in vitro, and markedly improved solubility and bioavailability compared with the SMART template (45a-c (PAT) vs 1 (SMART)).

Original languageEnglish (US)
Pages (from-to)4678-4693
Number of pages16
JournalJournal of Medicinal Chemistry
Volume54
Issue number13
DOIs
StatePublished - Jul 14 2011

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Thiazoles
Antineoplastic Agents
Solubility
Multiple Drug Resistance
P-Glycoprotein
Tubulin
Polymerization
Biological Availability
Pharmacokinetics
Cell Line
Water
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents. / Lu, Yan; Li, Chien Ming; Wang, Zhao; Chen, Jianjun; Mohler, Michael L.; Li, Wei; Dalton, James T.; Miller, Duane.

In: Journal of Medicinal Chemistry, Vol. 54, No. 13, 14.07.2011, p. 4678-4693.

Research output: Contribution to journalArticle

Lu, Yan ; Li, Chien Ming ; Wang, Zhao ; Chen, Jianjun ; Mohler, Michael L. ; Li, Wei ; Dalton, James T. ; Miller, Duane. / Design, synthesis, and SAR studies of 4-substituted methoxylbenzoyl-aryl- thiazoles analogues as potent and orally bioavailable anticancer agents. In: Journal of Medicinal Chemistry. 2011 ; Vol. 54, No. 13. pp. 4678-4693.
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AU - Dalton, James T.

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