Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations.
Pyrrolo[2,3- a]carbazole derivatives were synthesized, and their effects on CDK1/cyclinB activity were evaluated. The most potent and efficacious inhibitor was found to be ethyl 9-chloro-1H-pyrrolo[2,3-alpha]carbazole-2-carboxylate (1e), exhibiting an IC50 in the low micromolar range and leading to 90% at higher concentrations. Using a computational model for CDK1-1e, binding we have observed that 1e exhibited two likely binding modes in the ATP-binding cleft that involve interactions with Lys130, Thr14, and Asp146 of the enzyme.
Fousteris
Manolis A
MA
Laboratory of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, GR-26500 Rion, Patras, Greece.
Papakyriakou
Athanasios
A
Koutsourea
Anna
A
Manioudaki
Maria
M
Lampropoulou
Evgenia
E
Papadimitriou
Evangelia
E
Spyroulias
Georgios A
GA
Nikolaropoulos
Sotiris S
SS
D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D011485:Protein Binding; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D002227:Carbazoles; D011758:Pyrroles; D016203:CDC2 Protein Kinase