PUBLICATION
Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities
- Authors
- Romagnoli, R., Oliva, P., Prencipe, F., Manfredini, S., Budassi, F., Brancale, A., Ferla, S., Hamel, E., Corallo, D., Aveic, S., Manfreda, L., Mariotto, E., Bortolozzi, R., Viola, G.
- ID
- ZDB-PUB-220827-30
- Date
- 2022
- Source
- Pharmaceuticals (Basel, Switzerland) 15(8): (Journal)
- Registered Authors
- Aveic, Sanja, Corallo, Diana
- Keywords
- [1,2,4]triazolo[1,5-a]pyrimidine, antitumor activity, apoptosis, colchicine binding site, microtubule-targeting agents
- MeSH Terms
- none
- PubMed
- 36015179 Full text @ Pharmaceuticals (Basel)
Citation
Romagnoli, R., Oliva, P., Prencipe, F., Manfredini, S., Budassi, F., Brancale, A., Ferla, S., Hamel, E., Corallo, D., Aveic, S., Manfreda, L., Mariotto, E., Bortolozzi, R., Viola, G. (2022) Design, Synthesis and Biological Investigation of 2-Anilino Triazolopyrimidines as Tubulin Polymerization Inhibitors with Anticancer Activities. Pharmaceuticals (Basel, Switzerland). 15(8).
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.
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Human Disease / Model
Sequence Targeting Reagents
Fish
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