Syracuse

Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors

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Hauguel, Camille | Ducellier, Sarah | Provot, Olivier | Ibrahim, Nada | Lamaa, Diana | Balcerowiak, Coline | Letribot, Boris | Nascimento, Megane | Blanchard, Vincent | Askenatzis, Laurie | Levaique, Helene | Bignon, Jérôme | Baschieri, Francesco | Bauvais, Cyril | Bollot, Guillaume | Renko, Dolor | Deroussent, Alain | Prost, Bastien | Laisne, Marie-Catherine | Michallet, Sophie | Lafanechère, Laurence | Papot, Sébastien | Montagnac, Guillaume | Tran, Christine | Alami, Mouad | Apcher, Sebastien | Hamze, Abdallah

Edité par CCSD ; Elsevier -

International audience. A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.

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