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

Anja Beč,Lucija Hok,Els Vanstreels,Robert Vianello,Leentje Persoons,Dirk Daelemans,Marijana Hranjec

doi:10.3390/ph14101052

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.

Highlights

IntroductionMicrotubules, being key dynamic structural components in cells, have attracted considerable attention from medicinal chemists as targets for anticancer drug discovery [1,2,3]
The synthesis of novel N‐substituted, benzimidazole‐derived acrylonitriles 32–71 is illustrated in Scheme 1, starting from the ortho-chloronitrobenzenes 1–2
Synthesis, computational analysis, and antiproliferative evaluation of novel benzimidazole-derived acrylonitriles prepared by the cyclocondensation of the corresponding N-substituted 2-(cyanomethyl)-benzimidazoles with benzaldehyde and 2-methoxy, 2,4-dimethoxy, 3,4,5-trimethoxy, 4-N,N-dimethylamino, and 4-N,Ndiethylamino-substituted benzaldehydes

Summary

Introduction

Microtubules, being key dynamic structural components in cells, have attracted considerable attention from medicinal chemists as targets for anticancer drug discovery [1,2,3]. These protein biopolymers, formed through the polymerization of heterodimers of α- and β-tubulins, play an important role in cellular shape organization, cell division, mitosis, and intracellular movement. These products alter the dynamics of tubulin, such as the polymerization and depolymerization [5], by binding to specific sites on the tubulin heterodimers [6], of which the most important are those for paclitaxel, vinblastine, and colchicine; within the binding to the tubulin heterodimers, inhibitors could suppress tubulin dynamic instability and interfere with microtubule functions, including the mitotic spindle formation

Methods

Results

Conclusion