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• W3169201146 endingPage "113590" @default.
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• W3169201146 abstract "Microtubules (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-(1 H )2 H -benzo[ d ] [1,2,3]triazol-1(2)-yl)-3-( R )acrylonitrile ( 9a-j , 10e , 11a , b ) and ( E )-2-(1 H -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 treated with 9a showed a considerable antiproliferative effect, (IC50 = 3.2 μM), an increased number of cells in G2/M-phase, followed by an enhancement in cell division defects. Moreover, β-tubulin staining confirmed 9a as a MDA triggering tubulin disassembly, whereas colchicine- 9a competition assay suggested that compound 9a compete with colchicine for the binding site on tubulin. Then, the co-administration of compound 9a and an extrusion pump inhibitor (EPI) was investigated: the association resulted beneficial for the antiproliferative activity and compound 9a showed to be client of extrusion pumps. Finally, structural superimposition of different colchicine binding site inhibitors (CBIs) in clinical trial and our MDA, provided an additional confirmation of the targeting to the predicted binding site. Physicochemical, pharmacokinetic and druglikeness predictions were also conducted and all the newly synthesised derivatives showed to be drug-like molecules. • Docking studies validated newly designed benzotriazole derivatives. • Compounds showed an antiproliferative activity blocking cell cycle in G2/M phase. • Fluorescence analysis confirmed mechanism of action showing slowed cytokinesis. • Lead compound was proved to compete with colchicine in its binding site. • Co-administration with an EPI resulted beneficial against drug-resistant lines." @default.
• W3169201146 created "2021-06-22" @default.
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• W3169201146 date "2021-10-01" @default.
• W3169201146 modified "2023-09-24" @default.
• W3169201146 title "A comprehensive assessment of a new series of 5′,6′-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs)" @default.
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• W3169201146 doi "https://doi.org/10.1016/j.ejmech.2021.113590" @default.
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