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A comprehensive assessment of a new series of 5',6'-difluorobenzotriazole-acrylonitrile derivatives as microtubule targeting agents (MTAs).
Riu, Federico; Sanna, Luca; Ibba, Roberta; Piras, Sandra; Bordoni, Valentina; Scorciapino, M Andrea; Lai, Michele; Sestito, Simona; Bagella, Luigi; Carta, Antonio.
Afiliação
  • Riu F; Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy.
  • Sanna L; Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy.
  • Ibba R; Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy. Electronic address: ribba@uniss.it.
  • Piras S; Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy.
  • Bordoni V; Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy.
  • Scorciapino MA; Department of Chemical and Geological Sciences, University of Cagliari, S.P. 8 Km 0.700, 09042, Monserrato (CA), Italy.
  • Lai M; Retrovirus Centre, Department of Translational Medicine and New Technologies in Medicine and Surgery, University of Pisa, Strada Statale Del Brennero, 2, Pisa, Italy; CISUP - Centre for Instrumentation Sharing - University of Pisa, Lungarno Pacinotti 43, Pisa, Italy.
  • Sestito S; Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy.
  • Bagella L; Department of Biomedical Sciences, University of Sassari, Viale San Pietro 43/b, 07100, Sassari, Italy; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, 19122, USA. Electronic address: lbage
  • Carta A; Department of Chemistry and Pharmacy, University of Sassari, Via Vienna 2, 07100, Sassari, Italy.
Eur J Med Chem ; 222: 113590, 2021 Oct 15.
Article em En | MEDLINE | ID: mdl-34139625
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-(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 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, ß-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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triazóis / Acrilonitrila / Microtúbulos / Antineoplásicos Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Triazóis / Acrilonitrila / Microtúbulos / Antineoplásicos Limite: Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article