Synthesis and evaluation of 5-substituted 9-hydroxypyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones as check point 1 kinase inhibitors

The structure–activity relationship (SAR) of 5-substituted pyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione derivatives 5 was investigated for their potential as Chk1 inhibitors for possible chemo- and radio-potentiators in anticancer chemotherapies. In silico virtual screening helped to optimize the substituent on the phenyl ring, and led to identification of the m-carbamoyl group among the 117 analogues tested. Further optimization studies focusing on the docking model of 15 in the active site of Chk1 revealed that 32b (IC50 = 2.8 nM) was a more potent inhibitor than UNC-01.

Potent inhibitors of Check point kinase 1 have been developed by a structure-based drug design.Figure optionsDownload as PowerPoint slide