1. Identification of a new series of flavopiridol-like structures as kinase inhibitors with high cytotoxic potency
- Author
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Mouad Alami, Jean-Daniel Brion, Pascal Bonnet, Abdallah Hamze, Nada Ibrahim, Pierre Colas, Jean-François Peyrat, Thomas Robert, Samir Messaoudi, Jérôme Bignon, Stéphane Bach, Béatrice Josselin, Hélène Levaique, Biomolécules : Conception, Isolement, Synthèse (BioCIS), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-CY Cergy Paris Université (CY), Institut de Chimie Organique et Analytique (ICOA), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut de Chimie du CNRS (INC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Orléans (UO)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Fédération de recherche de Roscoff (FR2424), Station biologique de Roscoff (SBR), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Messaoudi, Samir
- Subjects
Stereochemistry ,[CHIM.THER] Chemical Sciences/Medicinal Chemistry ,Antineoplastic Agents ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Favopiridol ,01 natural sciences ,Thiosugars ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Thioether ,Piperidines ,Drug Discovery ,Tumor Cells, Cultured ,Structure–activity relationship ,Cytotoxic T cell ,Humans ,Cytotoxicity ,Kinase inhibition ,Protein Kinase Inhibitors ,030304 developmental biology ,Cell Proliferation ,Pharmacology ,chemistry.chemical_classification ,Flavonoids ,0303 health sciences ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Kinase ,Organic Chemistry ,[CHIM.CATA] Chemical Sciences/Catalysis ,General Medicine ,[CHIM.CATA]Chemical Sciences/Catalysis ,In vitro ,structure-activity relationship. Highlights ,0104 chemical sciences ,3. Good health ,Amino acid ,Molecular Docking Simulation ,chemistry ,cytotoxicity ,Drug Screening Assays, Antitumor ,Protein Kinases - Abstract
International audience; In this work, unique structure of flavopiridol analogs bearing thiosugars, amino acids and heterocyclic moieties tethered to the flavopiridol via thioether and amine bonds mainly on its C ring have been prepared. The analogs bearing thioether-benzimidazoles as substituents have demonstrated high cytotoxic activity in vitro against up to seven cancer cell lines. Their cytotoxic effects are comparable to those of flavopiridol. The most active compound (13c) found after the structure-activity relationship (SAR) showed the best antiproliferative activity and was more efficient than the reference compound. In addition, compound 13c showed significant nanomolar inhibition against CDK9 and GSK3β protein kinases.
- Published
- 2020
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