Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations

Manolis A Fousteris; Athanasios Papakyriakou; Anna Koutsourea; Maria Manioudaki; Evgenia Lampropoulou; Evangelia Papadimitriou; Georgios A Spyroulias; Sotiris S Nikolaropoulos

doi:10.1021/jm0700666

Pyrrolo[2,3-a]carbazoles as potential cyclin dependent kinase 1 (CDK1) Inhibitors. Synthesis, biological evaluation, and binding mode through docking simulations

J Med Chem. 2008 Feb 28;51(4):1048-52. doi: 10.1021/jm0700666. Epub 2008 Jan 31.

Authors

Manolis A Fousteris¹, Athanasios Papakyriakou, Anna Koutsourea, Maria Manioudaki, Evgenia Lampropoulou, Evangelia Papadimitriou, Georgios A Spyroulias, Sotiris S Nikolaropoulos

Affiliation

¹ Laboratory of Medicinal Chemistry, Department of Pharmacy, School of Health Sciences, University of Patras, GR-26500 Rion, Patras, Greece.

PMID: 18232654
DOI: 10.1021/jm0700666

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Binding Sites
CDC2 Protein Kinase / antagonists & inhibitors*
CDC2 Protein Kinase / chemistry
Carbazoles / chemical synthesis*
Carbazoles / chemistry
Models, Molecular*
Protein Binding
Pyrroles / chemical synthesis*
Pyrroles / chemistry
Structure-Activity Relationship

Substances

Carbazoles
Pyrroles
CDC2 Protein Kinase