Design and synthesis of poly ADP-ribose polymerase-1 inhibitors. 2. Biological evaluation of aza-5[H]-phenanthridin-6-ones as potent, aqueous-soluble compounds for the treatment of ischemic injuries

Dana Ferraris, Yao Sen Ko, Thomas Pahutski, Rica Pargas Ficco, Larisa Serdyuk, Christina Alemu, Chadwick Bradford, Tiffany Chiou, Randall Hoover, Shirley Huang, Susan Lautar, Shi Liang, Qian Lin, May X C Lu, Maria Mooney, Lisa Morgan, Yongzhen Qian, Scott Tran, Lawrence R. Williams, Qi Yi WuJie Zhang, Yinong Zou, Vincent Kalish

Research output: Contribution to journalArticlepeer-review

Abstract

A series of aza-5[H]-phenanthridin-6-ones were synthesized and evaluated as inhibitors of poly ADP-ribose polymerase-1 (PARP-1). Inhibitory potency of the unsubstituted aza-5[H]-phenanthridin-6-ones (i.e., benzonaphthyridones) was dependent on the position of the nitrogen atom within the core structure. The A ring nitrogen analogues (7-, 8-, and 10-aza-5[H]-phenanthridin6-ones) were an order of magnitude less potent than C ring nitrogen analogues (1-, 2-, 3-, and 4-aza-5[H]-phenanthridin-6-ones). Preliminary stroke results from 1- and 2-aza-5[H]-phenanthridin-6-one prompted structure-activity relationships to be established for several 2- and 3-substituted 1-aza-5[H]-phenanthridin-6-ones. The 2-substituted 1-aza-5[H]-phenanthridin-6-ones were designed to improve the solubility and pharmacokinetic profiles for this series of PARP-1 inhibitors. Most importantly, three compounds from this series demonstrated statistically significant protective effects in rat models of stroke and heart ischemia.

Original languageEnglish (US)
Pages (from-to)3138-3151
Number of pages14
JournalJournal of Medicinal Chemistry
Volume46
Issue number14
DOIs
StatePublished - Jul 3 2003
Externally publishedYes

ASJC Scopus subject areas

  • Organic Chemistry

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