Discovery of a Novel [6-6-5-5-6] Pentacyclic Tetrahydrocyclopentaphthalazinone as a Promising PARP Inhibitor Scaffold

Inhibitors of poly(ADP-ribose) polymerases (PARPs) have revolutionized the treatment of cancers with DNA repair deficiencies. Here we describe the structure-based discovery and synthesis of 6-6-5-5-6-fused pentacyclic scaffolds 5 and cis-(+/-)-6 as a novel class of PARP1 inhibitors. Chiral supercritical fluid chromatographic separation of cis-(+/-)-6 afforded inactive ent-6_P1 and active ent-6_P2. Compound 5 (P-gp ER = 0.9) and ent-6_P2 (P-gp ER = 1.1) demonstrated good Caco-2 permeability and are not actively effluxed by ABC transporters. In vitro analysis in HEK293T cells found that 5, cis-(+/-)-6, and ent-6_P2 showed near complete inhibition of PARP1 activity at 10 mu M. Furthermore, compounds 5, cis-(+/-)-6, and ent-6_P2 displayed selective cytotoxic activity in BRCA mutant cancer cells but not isogenic BRCA-proficient cells. Taken together, 5 and ent-6_P2 define a novel class of lead PARP inhibitors for further development.