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

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

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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