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Design, synthesis, and biological screening of a series of 4′-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs)
Riu, Federico Ibba, Roberta Zoroddu, Stefano Sestito, Simona Lai, Michele Piras, Sandra Sanna, Luca Bordoni, Valentina Carta, Antonia
Riu, Federico
Ibba, Roberta
Zoroddu, Stefano
Sestito, Simona
Lai, Michele
Piras, Sandra
Sanna, Luca
Bordoni, Valentina
Carta, Antonia
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Journal article
Date
2022-08-17
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Biology
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https://doi.org/10.1080/14756366.2022.2111680
Abstract
Introduction: Colchicine-binding site inhibitors are some of the most interesting ligands belonging to the wider family of microtubule-destabilising agents. Results: A novel series of 4′-fluoro-substituted ligands (5–13) was synthesised. The antiproliferative activity assays resulted in nM values for the new benzotriazole-acrylonitrile derivatives. Compound 5, the hit compound, showed an evident blockade of HeLa cell cycle in the G2-M phase, but also a pro-apoptotic potential, and an increase of early and late apoptotic cells in HeLa and MCF-7 cell cycle analysis. Confocal microscopy analysis showed a segmented shape and a collapse of the cytoskeleton, as well as a consistent cell shrinkage after administration of 5 at 100 nM. Derivative 5 was also proved to compete with colchicine at colchicine-binding site, lowering its activity against tubulin polymerisation. In addition, co-administration of 5 and doxorubicin in drug-resistant A375 melanoma cell line highlighted a synergic potential in terms of inhibition of cell viability. Discussion: The 4′-fluoro substitution of benzotriazole-acrylonitrile scaffold brought us a step forward in the optimisation process to obtain compound 5 as promising MDA antiproliferative agent at nanomolar concentration.
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Citation
Federico Riu, Roberta Ibba, Stefano Zoroddu, Simona Sestito, Michele Lai, Sandra Piras, Luca Sanna, Valentina Bordoni, Luigi Bagella & Antonio Carta (2022) Design, synthesis, and biological screening of a series of 4′-fluoro-benzotriazole-acrylonitrile derivatives as microtubule-destabilising agents (MDAs), Journal of Enzyme Inhibition and Medicinal Chemistry, 37:1, 2223-2240, DOI: 10.1080/14756366.2022.2111680
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Taylor and Francis Group
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Journal of Enzyme Inhibition and Medicinal Chemistry, Vol. 37
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