Synthesis of substituted 5[ H]phenanthridin-6-ones as potent poly(ADP-ribose)polymerase-1 (PARP1) inhibitors

1-, 2-, 3-, 4-, 8-, or 10-Substituted 5( H)phenanthridin-6-ones were synthesized and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC 50 values (compound 1b, 10 nM) but also desirable water solubility characteristics. These properties, which are superior to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds allows SAR analysis of favored substituents and substituted positions on 5( H)phenanthridin-6-one ring. 1-, 2-, 3-, 4-, 8-, or 10-Substituted 5( H)phenanthridin-6-ones were synthesized in three different pathways and found to be potent PARP1 inhibitors. Among the 28 compounds prepared, some showed not only low IC 50 values (compound 1b, 10 nM) against recombinant human PARP1 in vitro but also desirable water solubility characteristics.