Synthesis and structure–activity relationships of novel poly(ADP-ribose) polymerase-1 inhibitors

A series of novel pyrrolocarbazoles was synthesized as potential PARP-1 inhibitors. Pyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. Synthesis of analogs around this template with the aid of modeling studies led to the identification of the truncated imide 14. Compound 14 (IC50 = 40 nM), with deleted B-ring, was found to be an equipotent PARP-1 inhibitor.

Graphical abstractPyrrolocarbazole 1 was identified as a potent PARP-1 inhibitor (IC50 = 36 nM) from our internal database. The synthesis and SAR optimization around this template with the aid of modeling studies led to the identification of the truncated imide.Figure optionsDownload full-size imageDownload as PowerPoint slide