Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents

Jianjun Chen, Zhao Wang, Chien Ming Li, Yan Lu, Pavan K. Vaddady, Bernd Meibohm, James T. Dalton, Duane Miller, Wei Li

Research output: Contribution to journalArticle

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Abstract

A series of 2-aryl-4-benzoyl-imidazoles (ABI) was synthesized as a result of structural modifications based on the previous set of 2-aryl-imidazole-4- carboxylic amide (AICA) derivatives and 4-substituted methoxylbenzoyl-aryl- thiazoles (SMART). The average IC50 of the most active compound (5da) was 15.7 nM. ABI analogues have substantially improved aqueous solubility (48.9 μg/mL for 5ga vs 0.909 μg/mL for SMART-1, 0.137 μg/mL for paclitaxel, and 1.04 μg/mL for combretastatin A4). Mechanism of action studies indicate that the anticancer activity of ABI analogues is through inhibition of tubulin polymerization by interacting with the colchicine binding site. Unlike paclitaxel and colchicine, the ABI compounds were equally potent against multidrug resistant cancer cells and the sensitive parental melanoma cancer cells. In vivo results indicated that 5cb was more effective than DTIC in inhibiting melanoma xenograph tumor growth. Our results suggest that the novel ABI compounds may be developed to effectively treat drug-resistant tumors.

Original languageEnglish (US)
Pages (from-to)7414-7427
Number of pages14
JournalJournal of Medicinal Chemistry
Volume53
Issue number20
DOIs
StatePublished - Oct 28 2010

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Imidazoles
Colchicine
Tubulin
Antineoplastic Agents
Binding Sites
Thiazoles
Paclitaxel
Melanoma
Neoplasms
Dacarbazine
Amides
Polymerization
Solubility
Inhibitory Concentration 50
Growth
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents. / Chen, Jianjun; Wang, Zhao; Li, Chien Ming; Lu, Yan; Vaddady, Pavan K.; Meibohm, Bernd; Dalton, James T.; Miller, Duane; Li, Wei.

In: Journal of Medicinal Chemistry, Vol. 53, No. 20, 28.10.2010, p. 7414-7427.

Research output: Contribution to journalArticle

Chen, Jianjun ; Wang, Zhao ; Li, Chien Ming ; Lu, Yan ; Vaddady, Pavan K. ; Meibohm, Bernd ; Dalton, James T. ; Miller, Duane ; Li, Wei. / Discovery of novel 2-aryl-4-benzoyl-imidazoles targeting the colchicines binding site in tubulin as potential anticancer agents. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 20. pp. 7414-7427.
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