Pyrrolo[2,3-a]carbazoles as Potential Cyclin Dependent Kinase 1 (CDK1) Inhibitors. Synthesis, Biological Evaluation, and Binding Mode through Docking Simulations

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• 作者：Manolis A. Fousteris ; Athanasios Papakyriakou ; Anna Koutsourea ; Maria Manioudaki ; Evgenia Lampropoulou ; Evangelia Papadimitriou ; Georgios A. Spyroulias ; Sotiris S. Nikolaropoulos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：February 28, 2008
• 年：2008
• 卷：51
• 期：4
• 页码：1048 - 1052
• 全文大小：435K
• 年卷期：v.51,no.4(February 28, 2008)
• ISSN：1520-4804

文摘

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-α]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.