title: Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors.
abstract: New series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-ones and 3,4,5,10-tetrahydro-2H-diazepino[3,4-b]indol-1-ones have been synthesized through an iodolactonisation/lactone-to-lactam rearrangement sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 and GSK-3). 11-Iodo-2,3,4,5-tetrahydro[1,4]diazepino[1,2-a]indol-1-one derivatives exhibited sub-micromolar inhibitory activity against cyclin-dependent kinases. Docking studies were realized to determine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Our result highlighted two weak Van-der-Waals bonding interactions established between the iodine atom and both phenyl group of Phe 80 and ammonium end of Lys 33.
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR CNRS 5246, Université de Lyon, Université Claude Bernard - Lyon 1, Bâtiment Curien, 43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France.
authors.forename: Aurélien
authors.initials: A
authors.lastname: Putey
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR CNRS 5246, Université de Lyon, Université Claude Bernard - Lyon 1, Bâtiment Curien, 43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Fournet
authors.affiliation: CNRS, USR3151, 'Protein Phosphorylation & Human Disease' Group, Station Biologique, BP 74, 29680 Roscoff, Bretagne, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Lozach
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR CNRS 5246, Université de Lyon, Université Claude Bernard - Lyon 1, Bâtiment Curien, 43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France; Université de Toulouse et CNRS, INSA, UPS, UMR 5215, LPCNO, 135 Avenue de Rangueil, F-31077 Toulouse, France. Electronic address: lionel.perrin@univ-lyon1.fr.
authors.forename: Lionel
authors.initials: L
authors.lastname: Perrin
authors.affiliation: CNRS, USR3151, 'Protein Phosphorylation & Human Disease' Group, Station Biologique, BP 74, 29680 Roscoff, Bretagne, France; ManRos Therapeutics, Hôtel de Recherche, Centre de Perharidy, 29680 Roscoff, Bretagne, France. Electronic address: meijer@sb-roscoff.fr.
authors.forename: Laurent
authors.initials: L
authors.lastname: Meijer
authors.affiliation: Institut de Chimie et Biochimie Moléculaires et Supramoléculaires UMR CNRS 5246, Université de Lyon, Université Claude Bernard - Lyon 1, Bâtiment Curien, 43 Boulevard du 11 novembre 1918, F-69622 Villeurbanne, France. Electronic address: benoit.joseph@univ-lyon1.fr.
authors.forename: Benoît
authors.initials: B
authors.lastname: Joseph
mesh_terms: D000818:Animals; D020134:Catalytic Domain; D060326:Chemistry Techniques, Synthetic; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D007211:Indoles; D047428:Protein Kinase Inhibitors; D018844:Cyclin-Dependent Kinases
keywords: CDK; Docking; GSK-3; Indole; Inhibitor; Iodolactonisation; Kinase