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N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis

Perin, Nataša; Hok, Lucija; Beč, Anja; Persoons, Leentje; Vanstreels, Els; Daelemans, Dirk; Vianello, Robert; Hranjec, Marijana (2020) N-substituted benzimidazole acrylonitriles as in vitro tubulin polymerization inhibitors: Synthesis, biological activity and computational analysis. European journal of medicinal chemistry, 211 . ISSN 0223-5234

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We present the design, synthesis and biological activity of novel N-substituted benzimidazole based acrylonitriles as potential tubulin polymerization inhibitors. Their synthesis was achieved using classical linear organic and microwave assisted techniques, starting from aromatic aldehydes and N-substituted-2- cyanomethylbenzimidazoles. All newly prepared compounds were tested for their antiproliferative activity in vitro on eight human cancer cell lines and one reference non-cancerous assay. N,N- dimethylamino substituted acrylonitriles 30 and 41, bearing N-isobutyl and cyano substituents placed on the benzimidazole nuclei, showed strong and selective antiproliferative activity in the submicromolar range of inhibitory concentrations (IC50 0.2–0.6 μM), while being significantly less toxic than reference systems docetaxel and staurosporine, thus promoting them as lead compounds. Mechanism of action studies demonstrated that two most active compounds inhibited tubulin polymerization. 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 activities, and demonstrated that E-isomers are active substances. It also provided structural determinants affecting both the binding position and the matching affinities, identifying the attached NMe2 group as the most dominant in promoting the binding, which allows ligands to optimize favourable cation∙∙∙π and hydrogen bonding interactions with Lys352.

Item Type: Article
Uncontrolled Keywords: acrylonitriles ; amination ; antiproliferative activity ; benzimidazoles ; docking simulations ; tubulin polymerization
Subjects: NATURAL SCIENCES > Chemistry
NATURAL SCIENCES > Chemistry > Theoretical Chemistry
NATURAL SCIENCES > Chemistry > Organic Chemistry
NATURAL SCIENCES > Chemistry > Applied Chemistry
Divisions: Division of Organic Chemistry and Biochemistry
Project titleProject leaderProject codeProject type
Istraživanje antioksidativnog djelovanja benzazolskog skeleta u dizajnu novih antitumorskih agensaHranjec, MarijanaIP-2018-01-4379HRZZ
Depositing User: Robert Vianello
Date Deposited: 08 Dec 2022 10:52
DOI: 10.1016/j.ejmech.2020.113003

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