Article ID Journal Published Year Pages File Type
1377316 Bioorganic & Medicinal Chemistry Letters 2008 5 Pages PDF
Abstract

Pyrrolo[3,4-c]carbazoles bearing solubilising basic side chains at the 8-position retain potent Wee1 and Chk1 inhibitory properties in isolated enzyme assays, and evidence of G2/M checkpoint abrogation in several cellular assays. Co-crystal structure studies confirm that the primary binding to the Wee1 enzyme is as described previously, with the C-8 side chains residing in an area of bulk tolerance.

Graphical abstract8-Substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones are potent, soluble inhibitors of Wee1 and Chk1 kinases. They inhibited the alkylator-induced phosphorylation of Cdc2 Tyr15 and abrogated the G2/M checkpoint in HT-29 cells, thus substantially enhancing the cytotoxicity of the DNA-damaging agent cisplatin.Figure optionsDownload full-size imageDownload as PowerPoint slide

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