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

  • Eur J Med Chem. 2022 Oct 5;240:114573. doi: 10.1016/j.ejmech.2022.114573.
Camille Hauguel  1 ,  Sarah Ducellier  2 ,  Olivier Provot  1 ,  Nada Ibrahim  1 ,  Diana Lamaa  1 ,  Coline Balcerowiak  1 ,  Boris Letribot  1 ,  Megane Nascimento  2 ,  Vincent Blanchard  1 ,  Laurie Askenatzis  3 ,  Helene Levaique  3 ,  Jérôme Bignon  3 ,  Francesco Baschieri  4 ,  Cyril Bauvais  5 ,  Guillaume Bollot  5 ,  Dolor Renko  1 ,  Alain Deroussent  6 ,  Bastien Prost  7 ,  Marie-Catherine Laisne  8 ,  Sophie Michallet  8 ,  Laurence Lafanechère  8 ,  Sébastien Papot  9 ,  Guillaume Montagnac  4 ,  Christine Tran  1 ,  Mouad Alami  1 ,  Sebastien Apcher  2 ,  Abdallah Hamze  10
Affiliations
  • 1. Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France.
  • 2. Université Paris-Saclay, Institut Gustave Roussy, Inserm, Immunologie anti-tumorale et immunothérapie des cancers, 94805, Villejuif, France.
  • 3. Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, 91198, Gif-sur-Yvette, France.
  • 4. Université Paris-Saclay, Inserm, Institut Gustave Roussy, Dynamique des cellules tumorales, 94805, Villejuif, France.
  • 5. SYNSIGHT, 91400, Orsay, France.
  • 6. Université Paris-Saclay, CNRS, Institut Gustave Roussy, Aspects métoboliques et systémiques de l'oncogenèse pour de nouvelles approches thérapeutiques, 94805, Villejuif, France.
  • 7. Université Paris-Saclay, Inserm, CNRS, Ingénierie et Plateformes au service de l'innovation thérapeutique, 92296, Châtenay-Malabry, France.
  • 8. Université Grenoble Alpes, Inserm, CNRS, Institute for Advanced Biosciences, 38000, Grenoble, France.
  • 9. Université de Poitiers, CNRS, Institut de Chimie des Milieux et des Matériaux de Poitiers (IC2MP), 86073, Poitiers, France.
  • 10. Université Paris-Saclay, CNRS, BioCIS, 92290, Châtenay-Malabry, France. Electronic address: [email protected].
PMID: 35797900 DOI: 10.1016/j.ejmech.2022.114573
Abstract

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.

Keywords
Cancer; Cytotoxicity; HDACi; Multitargeted compounds; Tubulin.
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