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 synthes ized and found to be potent PARP1 inhibitors. Among the 28 compounds prepar ed. some showed not only low IC50 values (compound 1b, 10 nM) but also desi rable water solubility characteristics. These properties, which are superio r to the common PARP1 inhibitors such as benzamides and isoquinolin-1-ones, are essential for potential therapeutic usage. The variety of compounds al lows SAR analysis of favored substituents and substituted positions on 5(H) phenanthridin-6-one ring. (C) 2001 Elsevier Science Ltd. All rights reserve d.