A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs)

Eur J Med Chem. 2021 Jun 1;222:113590. doi: 10.1016/j.ejmech.2021.113590. Online ahead of print.ABSTRACTMicrotubules (MTs) are the principal target for drugs acting against mitosis. These compounds, called microtubule targeting agents (MTAs), cause a mitotic arrest during G2/M phase, subsequently inducing cell apoptosis. MTAs could be classified in two groups: microtubule stabilising agents (MSAs) and microtubule destabilising agents (MDAs). In this paper we present a new series of (E) (Z)-2-(5,6-difluoro-(1H)2H-benzo[d] [1,2,3]triazol-1(2)-yl)-3-(R)acrylonitrile (9a-j, 10e, 11a,b) and (E)-2-(1H-benzo[d] [1,2,3]triazol-1-yl)-3-(R)acrylonitrile derivatives (13d,j), which were recognised to act as MTAs agents. They were rationally designed, synthesised, characterised and subjected to different biological assessments. Computational docking was carried out in order to investigate the potential binding to the colchicine-binding site on tubulin. From this first prediction, the di-fluoro substitution seemed to be beneficial for the binding affinity with tubulin. The new fluorine derivatives, here presented, showed an improved antiproliferative activity when compared to the previously reported compounds. The biological evaluation included a preliminary antiproliferative screening on NCI60 cancer cells panel (1-10 μM). Compound 9a was selected as lead compound of the new series of derivatives. The in vitro XTT assay, flow cytometry analysis and immunostaining performed on HeLa cells ...
Source: European Journal of Medicinal Chemistry - Category: Chemistry Authors: Source Type: research