Design, Synthesis, and Anti-tumor Activity of Novel 2-Aryl Benzimidazole Compounds

Author(s):

Haimiti Xiaohelaiti, Wenping Wu, Yiting Gao, Sisi Li and Cheng Ma*   Pages 1644 - 1651 ( 8 )

Abstract:

<p> Background: Combretastatin A-4 (CA-4) is a natural product isolated from the bark of the South African bush willow tree <i>Combretum caffrum</i>, which exerts tubulin inhibition, but its clinical application is limited due to poor stability and water solubility. 2-aryl benzimidazoles are excellent pharmacological skeletons with many activities, especially in tumor inhibition, and better pharmacokinetic properties. Several scaffold CA-4 analogs have been synthesized to date possessing antitumor activities. </p><p> Objective: The benzimidazole was applied as the core moiety to replace the B ring and unstable linkage of CA-4, and the 5-aryl acetenyl group was introduced to improve the antitumor activity. MCF-7, A549, Caco-2, Siha, and Eca-109 tumor cell lines were used to study inhibition by these agents <i>in vitro</i>. </p><p> Methods: The benzimidazole structure was constructed from the oxidation of o-nitroaniline and aldehyde and the following schemes, and the structural characterization was carried out. The antitumor effects were evaluated <i>in vitro</i> through MTT assay, cell cycle arrest, and apoptosis assay. Molecular docking with tubulin (Protein ID: 1SA0) was analyzed for the structure-activity relationship. </p><p> Results: Among these derivatives, 4a-4h series (with 6-methoxy group) compounds inhibited the tumor cell lines much stronger than the CA-4 and cisplatin, especially compound 4f showed prominently inhibitory activity in Siha cell with IC₅₀ value as 0.61 μmol/L. The further assay showed that the cell cycle was arrested at the G₀/G₁ phase as well verified in apoptosis assay. Molecular docking indicated that 4f had stronger affinity energy and hydrogen bond than CA-4. </p><p> Conclusion: The compound 4f has the potency to be used as an anti-tubulin agent and the 2-trimethoxyphenyl benzimidazole skeleton deserves further study as an antitumor structure.</p>

Keywords:

CA-4, synthesis, benzimidazole, antiproliferative, PI3K, tubulin.

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