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Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2

Beč, Anja; Hok, Lucija; Persoons, Leentje; Vanstreels, Els; Daelemans, Dirk; Vianello, Robert; Hranjec, Marijana (2021) Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2. Pharmaceuticals, 14 . pp. 1052-1078. ISSN 1424-8247

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Abstract

We used classical linear and microwave-assisted synthesis methods to prepare novel Nsubstituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin’s -subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.

Item Type: Article
Uncontrolled Keywords: acrylonitriles ; antiproliferative activity ; benzimidazoles ; docking analysis ; molecular dynamics simulations ; tubulin polymerization
Subjects: NATURAL SCIENCES > Biology
Divisions: Division of Organic Chemistry and Biochemistry
Projects:
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: 15 Nov 2021 10:03
Last Modified: 15 Nov 2021 10:04
URI: http://fulir.irb.hr/id/eprint/6707
DOI: 10.3390/ph14101052

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