Design, synthesis and biological investigation of 2-anilino triazolopyrimidines as tubulin polymerization inhibitors with anticancer activities

Romagnoli, Romeo, Oliva, Paola, Prencipe, Filippo, Manfredini, Stefano, Budassi, Federica, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, Ferla, Salvatore ORCID: https://orcid.org/0000-0002-5918-9237, Hamel, Ernest, Corallo, Diana, Aveic, Sanja, Manfreda, Lorenzo, Mariotto, Elena, Bortolozzi, Roberta and Viola, Giampietro 2022. Design, synthesis and biological investigation of 2-anilino triazolopyrimidines as tubulin polymerization inhibitors with anticancer activities. Pharmaceuticals 15 (8) , e1031. 10.3390/ph15081031

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Abstract

A further investigation aiming to generate new potential antitumor agents led us to synthesize a new series of twenty-two compounds characterized by the presence of the 7-(3′,4′,5′-trimethoxyphenyl)-[1, 2,4]triazolo[1,5-a]pyrimidine pharmacophore modified at its 2-position. Among the synthesized compounds, three were significantly more active than the others. These bore the substituents p-toluidino (3d), p-ethylanilino (3h) and 3′,4′-dimethylanilino (3f), and these compounds had IC50 values of 30−43, 160−240 and 67−160 nM, respectively, on HeLa, A549 and HT-29 cancer cells. The p-toluidino derivative 3d was the most potent inhibitor of tubulin polymerization (IC50: 0.45 µM) and strongly inhibited the binding of colchicine to tubulin (72% inhibition), with antiproliferative activity superior to CA-4 against A549 and HeLa cancer cell lines. In vitro investigation showed that compound 3d was able to block treated cells in the G2/M phase of the cell cycle and to induce apoptosis following the intrinsic pathway, further confirmed by mitochondrial depolarization and caspase-9 activation. In vivo experiments conducted on the zebrafish model showed good activity of 3d in reducing the mass of a HeLa cell xenograft. These effects occurred at nontoxic concentrations to the animal, indicating that 3d merits further developmental studies.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Pharmacy
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by/4.0/
Publisher:	MDPI
Date of First Compliant Deposit:	23 August 2022
Date of Acceptance:	17 August 2022
Last Modified:	05 Jan 2024 05:51
URI:	https://orca.cardiff.ac.uk/id/eprint/152120

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