Synthesis and structure–activity relationships of soluble 8-substituted 4-(2-chlorophenyl)-9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as inhibitors of the Wee1 and Chk1 checkpoint kinases

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.

8-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 as PowerPoint slide