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

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

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

15 Citations (Scopus)

Résumé

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.

langue originaleAnglais
Numéro d'article114573
journalEuropean Journal of Medicinal Chemistry
Volume240
Les DOIs
étatPublié - 5 oct. 2022
Modification externeOui

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