Synthesis and Biological Evaluation of Highly Active 7-Anilino Triazolopyrimidines as Potent Antimicrotubule Agents
Paola Oliva,
Romeo Romagnoli,
Barbara Cacciari,
Stefano Manfredini,
Chiara Padroni,
Andrea Brancale,
Salvatore Ferla,
Ernest Hamel,
Diana Corallo,
Sanja Aveic,
Noemi Milan,
Elena Mariotto,
Giampietro Viola,
Roberta Bortolozzi
Affiliations
Paola Oliva
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Romeo Romagnoli
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Barbara Cacciari
Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, 44121 Ferrara, Italy
Stefano Manfredini
Department of Life Sciences and Biotechnology, University of Ferrara, 44121 Ferrara, Italy
Chiara Padroni
Medicinal Chemistry Department, Integrated Drug Discovery, Aptuit—An Evotec Company, Via A. Fleming, 37135 Verona, Italy
Andrea Brancale
School of Pharmacy and Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK
Salvatore Ferla
Swansea University Medical School, Institute of Life Sciences 2, Swansea University, Swansea SA2 8PP, UK
Ernest Hamel
Molecular Pharmacology Branch, Developmental Therapeutics Program, Division of Cancer Treatment and Diagnosis, Frederick National Laboratory for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA
Diana Corallo
Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, Padova, Corso Stati Uniti 4, 35128 Padova, Italy
Sanja Aveic
Laboratory of Target Discovery and Biology of Neuroblastoma, Istituto di Ricerca Pediatrica (IRP), Fondazione Città della Speranza, Padova, Corso Stati Uniti 4, 35128 Padova, Italy
Noemi Milan
Hemato-Oncology Lab, Department of Woman’s and Child’s Health, University of Padova, 35131 Padova, Italy
Elena Mariotto
Hemato-Oncology Lab, Department of Woman’s and Child’s Health, University of Padova, 35131 Padova, Italy
Giampietro Viola
Hemato-Oncology Lab, Department of Woman’s and Child’s Health, University of Padova, 35131 Padova, Italy
Roberta Bortolozzi
Hemato-Oncology Lab, Department of Woman’s and Child’s Health, University of Padova, 35131 Padova, Italy
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.
