Discovery of Novel 2-aryl-4-benzoyl-imidazoles Targeting the Colchicines Binding Site in Tubulin As Potential Anticancer Agents

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2010 Oct 6

PMID 20919720

Citations 36

Authors

Jianjun Chen

Zhao Wang

Chien-Ming Li

Yan Lu

Pavan K Vaddady

Bernd Meibohm

James T Dalton

Duane D Miller

Wei Li

Affiliations

Soon will be listed here.

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 IC(50) 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.

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