Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors

Putey Aurelien (1) , Fournet Guy (2) , Olivier Lozach (3) , Lionel Perrin (4, 1) , Meijer Laurent (5, 3) , Joseph Benoît (2)

1 ICBMS - Institut de Chimie et Biochimie Moléculaires et Supramoléculaires
2 SMITh - Synthèse de Molécules d'Intérêt Thérapeutique
3 P3H - Phophorylation de protéines et Pathologies Humaines
4 LPCNO - Laboratoire de physique et chimie des nano-objets
5 ManRos Therapeutics

New series of 2,3,4,5-tetrahydro[1,4]diazepino[1,2a]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 rearrange-ment sequence. These compounds were evaluated as potential protein kinase inhibitors (CDK1, CDK5 andGSK-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 todetermine the binding mode of the inhibitors into the ATP binding domain of the CDK5 catalytic site. Ourresult highlighted two weak Van-der-Waals bonding interactions established between the iodine atomand both phenyl group of Phe 80 and ammonium end of Lys 33

Domaines: Chimie organique

Putey Aurelien, Fournet Guy, Olivier Lozach, Lionel Perrin, Meijer Laurent, et al.. Synthesis and biological evaluation of tetrahydro[1,4]diazepino[1,2-a]indol-1-ones as cyclin-dependent kinase inhibitors. European Journal of Medicinal Chemistry, 2014, 83, pp.617-629. ⟨hal-01147615⟩