engleski

N-substituted benzimidazoles as tubulin polymerization inhibitors

The benzimidazole scaffold, as a small nitrogen-containing heterocycle, has become a fundamental building block widely incorporated in the structure of numerous synthetic molecules. Due to the fact that benzimidazole nucleus is a bioisoster of the naturally occurring purine, its derivatives may interact with different biomolecules and achieve many biological effects, of which the most important is their promising and strong antiproliferative activity [1]. In this work, the novel N- substituted-2- benzimidazolyl acrylonitriles were synthesized and tested for the antiproliferative activity in vitro on eight human cancer cell lines and one reference non- cancerous assay. Of all evaluated derivatives, the N, N-dimethylamino substituted acrylonitriles bearing N-isobutyl and cyano moieties showed the strongest and the most selective antitumor activity in the submicromolar range of inhibitory concentrations, while being significantly less toxic than the reference systems docetaxel and staurosporine. Further mechanistic studies demonstrated that the most active derivatives inhibit cancer cell proliferation by disintegration of the microtubule network, comparable with the effect of the microtubule destabilizing compounds vincristine and colchicine. With the aim of obtaining a deeper insight into the binding of the tested molecules, we employed docking simulations and quantum- chemical calculations using the SwissDock web server and the Gaussian 16 software. Computational analysis confirmed the suitability of the employed benzimidazole- acrylonitrile skeleton for the binding within the colchicine binding site in tubulin, thus rationalizing the observed antitumor activity. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached N, N-dimethylamino group as the most dominant in promoting the binding, which allows ligands to optimize favorable cation∙∙∙π and hydrogen bonding interactions with Lys352. This initial research represents a valuable foundation for the further development and the rational design of the benzimidazole-based antiproliferative substances. [1] W. Akhtar, M. Faraz Khan, G. Verma, M. Shaquiquzzaman, M. A. Rizvi, S. H. Mehdi, M. Akhter, M. Mumtaz Alam, Therapeutic evolution of benzimidazole derivatives in the last quinquennial period, Eur. J. Med. Chem. 126 (2017) 705–753. DOI: 10.1016/j.ejmech.2016.12.010

acrylonitriles ; amination ; antiproliferative activity ; benzimidazoles ; docking simulations ; tubulin polymerization

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