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Issue 31, 2018
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Synthesis and biological evaluation of 2-aryl-benzimidazole derivatives of dehydroabietic acid as novel tubulin polymerization inhibitors

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Abstract

A series of novel 2-aryl-benzimidazole derivatives of dehydroabietic acid were synthesized and characterized by IR, 1H NMR, 13C NMR, MS and elemental analyses. All the target compounds were evaluated for their in vitro cytotoxic activity against SMMC-7721, MDA-MB-231, HeLa and CT-26 cancer cell lines and the normal hepatocyte cell line QSG-7701 through MTT assays. Among them, compound 6j displayed the most potent cytotoxic activity with IC50 values of 0.08 ± 0.01, 0.19 ± 0.04, 0.23 ± 0.05 and 0.42 ± 0.07 μM, respectively, and substantially reduced cytotoxicity against QSG-7701 cells (5.82 ± 0.38 μM). The treatment of SMMC-7721 cells with compound 6j led to considerable inhibition of cell migration ability. The influence of compound 6j on cell cycle distribution was assessed on SMMC-7721 cells, exhibiting a cell cycle arrest at the G2/M phase. Moreover, tubulin polymerization assays and immunofluorescence assays elucidated that compound 6j could significantly inhibit tubulin polymerization and disrupt the intracellular microtubule network. A molecular docking study provided insight into the binding mode of compound 6j in the colchicine site of tubulin. In addition, compound 6j was found to induce apoptosis of SMMC-7721 cells, an increase of intracellular ROS level and a loss of mitochondrial membrane potential in a dose-dependent manner. These findings provided new molecular scaffolds for the further development of novel antitumor agents targeting tubulin polymerization.

Graphical abstract: Synthesis and biological evaluation of 2-aryl-benzimidazole derivatives of dehydroabietic acid as novel tubulin polymerization inhibitors

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Supplementary files

Article information


Submitted
08 Mar 2018
Accepted
30 Apr 2018
First published
16 May 2018

This article is Open Access

RSC Adv., 2018,8, 17511-17526
Article type
Paper

Synthesis and biological evaluation of 2-aryl-benzimidazole derivatives of dehydroabietic acid as novel tubulin polymerization inhibitors

T. Miao, X. Tao, D. Li, H. Chen, X. Jin, Y. Geng, S. Wang and W. Gu, RSC Adv., 2018, 8, 17511 DOI: 10.1039/C8RA02078G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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