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Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
Pharmaceutics, Volume: 14, Issue: 6, Start page: 1191
Swansea University Author: Salvatore Ferla
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Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29...
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Two different series of fifty-two compounds, based on 3′,4′,5′-trimethoxyaniline (7a–ad) and variably substituted anilines (8a–v) at the 7-position of the 2-substituted-[1,2,4]triazolo [1,5-a]pyrimidine nucleus, had moderate to potent antiproliferative activity against A549, MDA-MB-231, HeLa, HT-29 and Jurkat cancer cell lines. All derivatives with a common 3-phenylpropylamino moiety at the 2-position of the triazolopyrimidine scaffold and different halogen-substituted anilines at its 7-position, corresponding to 4′-fluoroaniline (8q), 4′-fluoro-3′-chloroaniline (8r), 4′-chloroaniline (8s) and 4′-bromoaniline (8u), displayed the greatest antiproliferative activity with mean IC50′s of 83, 101, 91 and 83 nM, respectively. These four compounds inhibited tubulin polymerization about 2-fold more potently than combretastatin A-4 (CA-4), and their activities as inhibitors of [3H]colchicine binding to tubulin were similar to that of CA-4. These data underlined that the 3′,4′,5′-trimethoxyanilino moiety at the 7-position of the [1,2,4]triazolo [1,5-a]pyrimidine system, which characterized compounds 7a–ad, was not essential for maintaining potent antiproliferative and antitubulin activities. Compounds 8q and 8r had high selectivity against cancer cells, and their interaction with tubulin led to the accumulation of HeLa cells in the G2/M phase of the cell cycle and to apoptotic cell death through the mitochondrial pathway. Finally, compound 8q significantly inhibited HeLa cell growth in zebrafish embryos.
Data Availability Statement: Data supporting the reported results are available on request from thecorresponding authors.
antimitotic agents; structure–activity relationship; [1,2,4]triazolo [1,5-a]pyrimidine; antiproliferative activity; tubulin polymerization
Swansea University Medical School
R.R., B.C. 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 partfunded 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.