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

doi:10.3390/ph14101052

Open AccessArticle

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

by

Anja Beč

^1,†,

Lucija Hok

^2,†

,

Leentje Persoons

³

,

Els Vanstreels

³,

Dirk Daelemans

³,

Robert Vianello

^2,*

and

Marijana Hranjec

^1,*

¹

Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Marulićev trg 19, HR-10000 Zagreb, Croatia

²

Laboratory for the Computational Design and Synthesis of Functional Materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54, HR-10000 Zagreb, Croatia

³

KU Leuven, Department of Microbiology, Immunology and Transplantation, Laboratory of Virology and Chemotherapy, Rega Institute, 3000 Leuven, Belgium

^*

Authors to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Pharmaceuticals 2021, 14(10), 1052; https://doi.org/10.3390/ph14101052

Submission received: 6 September 2021 / Revised: 9 October 2021 / Accepted: 13 October 2021 / Published: 17 October 2021

(This article belongs to the Section Medicinal Chemistry)

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Abstract

We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, 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 β-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.

Keywords: acrylonitriles; antiproliferative activity; benzimidazoles; docking analysis; molecular dynamics simulations; tubulin polymerization

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MDPI and ACS Style

Beč, A.; Hok, L.; Persoons, L.; Vanstreels, E.; Daelemans, D.; Vianello, R.; Hranjec, M. Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2. Pharmaceuticals 2021, 14, 1052. https://doi.org/10.3390/ph14101052

AMA Style

Beč A, Hok L, Persoons L, Vanstreels E, Daelemans D, Vianello R, Hranjec M. Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2. Pharmaceuticals. 2021; 14(10):1052. https://doi.org/10.3390/ph14101052

Chicago/Turabian Style

Beč, Anja, Lucija Hok, Leentje Persoons, Els Vanstreels, Dirk Daelemans, Robert Vianello, and Marijana Hranjec. 2021. "Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2" Pharmaceuticals 14, no. 10: 1052. https://doi.org/10.3390/ph14101052

APA Style

Beč, A., Hok, L., Persoons, L., Vanstreels, E., Daelemans, D., Vianello, R., & Hranjec, M. (2021). Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2. Pharmaceuticals, 14(10), 1052. https://doi.org/10.3390/ph14101052

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

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