Synthesis of pyrazolo[4,3-a]phenanthridines, a new scaffold for Pim kinase inhibition

Virginie Suchaud (1) , Laurent Gavara (1, 2) , Francis Giraud (1) , Lionel Nauton (1) , Vincent Théry (1) , Fabrice Anizon (1) , Pascale Moreau (1)

1 ICCF - Institut de Chimie de Clermont-Ferrand
2 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

A new series of nitro or amino substituted pyrazolo[4,3-a]phenanthridines was synthesized in 6 steps from 5-bromo-6-nitroindazole. The evaluation of their inhibitory potency toward Pim kinases demonstrated that the nitro series could be considered as an interesting starting point for the development of new Pim kinase inhibitors, especially Pim-3. A preferential binding mode was suggested by molecular modeling experiments for nitro series and Pim-1/Pim-3 ATP-binding sites. Moreover, the most active compounds exhibited antiproliferative activities toward PC3 cells in the micromolar range.

Mots clés: Pyrazolo[4; 3-a]phenanthridines; Kinase inhibitors; Pim kinases; In vitro antiproliferative activities

Domaines: Chimie

Virginie Suchaud, Laurent Gavara, Francis Giraud, Lionel Nauton, Vincent Théry, et al.. Synthesis of pyrazolo[4,3-a]phenanthridines, a new scaffold for Pim kinase inhibition. Bioorganic and Medicinal Chemistry, 2014, 22, pp.4704-4710. ⟨10.1016/j.bmc.2014.07.011⟩. ⟨hal-01077451⟩