Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors - UNICANCER Accéder directement au contenu
Article Dans Une Revue European Journal of Medicinal Chemistry Année : 2022

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

Jérôme Bignon
Cyril Bauvais
  • Fonction : Auteur
Guillaume Bollot
  • Fonction : Auteur

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.
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Dates et versions

hal-03752715 , version 1 (23-11-2022)

Identifiants

Citer

Camille Hauguel, Sarah Ducellier, Olivier Provot, Nada Ibrahim, Diana Lamaa, et al.. Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors. European Journal of Medicinal Chemistry, 2022, 240, pp.114573. ⟨10.1016/j.ejmech.2022.114573⟩. ⟨hal-03752715⟩
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