Journal article 37 views 4 downloads
Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
Pharmaceuticals, Volume: 15, Issue: 8, Start page: 1031
Swansea University Author: Salvatore Ferla
PDF | Version of Record
© 2022 by the authors. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) licenseDownload (4.01MB)
DOI (Published version): 10.3390/ph15081031
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 comp...
Check full text
No Tags, Be the first to tag this record!
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.
colchicine binding site; antitumor activity; [1,2,4]triazolo[1,5-a]pyrimidine; apoptosis; microtubule-targeting agents
Faculty of Medicine, Health and Life Sciences
R.R. and S.M. acknowledge the support of the Ministero dell’Istruzione-MIUR, PRIN
2017, by grant 2017E84AA4_002. S.F. is supported by the Sêr Cymru II program, which is partially
funded by Swansea University and the European Regional Development Fund through the Welsh
Government. This research was supported in part by the Developmental Therapeutics Program in
the Division of Cancer Treatment and Diagnosis of the National Cancer Institute, which includes
federal funds under Contract No. HHSN261200800001E.