5-Benzamidoisoquinolin-1-ones and 5-(ω-Carboxyalkyl)isoquinolin-1-ones as Isoform-Selective Inhibitors of Poly(ADP-ribose) Polymerase 2 (PARP-2)

• Published in: Journal of medicinal chemistry 2011-04, Vol.54 (7), p.2049-2059
• Main Authors: Sunderland, Peter T, Woon, Esther C. Y, Dhami, Archana, Bergin, Aoife B, Mahon, Mary F, Wood, Pauline J, Jones, Louise A, Tully, Sophie R, Lloyd, Matthew D, Thompson, Andrew S, Javaid, Hashim, Martin, Niall M. B, Threadgill, Michael D
• Format: Article
• Language: English
• Subjects: Animals; Cell Line, Tumor; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Hydrogen Bonding; Inhibitory Concentration 50; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Lactams - chemistry; Mice; Models, Molecular; Oxygen - chemistry; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases - chemistry; Protein Conformation; Substrate Specificity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm1010918

PARP-2 is a member of the poly(ADP-ribose) polymerase family, with some activities similar to those of PARP-1 but with other distinct roles. Two series of isoquinolin-1-ones were designed, synthesized, and evaluated as selective inhibitors of PARP-2, using the structures of the catalytic sites of the isoforms. A new efficient synthesis of 5-aminoisoquinolin-1-one was developed, and acylation with acyl chlorides gave 5-acylaminoisoquinolin-1-ones. By examination of isoquinolin-1-ones with carboxylates tethered to the 5-position, Heck coupling of 5-iodoisoquinolin-1-one furnished the 5-CHCHCO2H compound for reduction to the 5-propanoic acid. Alkylation of 5-aminoisoquinolin-1-one under mildly basic conditions, followed by hydrolysis, gave 5-(carboxymethylamino)isoquinolin-1-one, whereas it was alkylated at 2-N with methyl propenoate and strong base. Compounds were assayed in vitro for inhibition of PARP-1 and PARP-2, using FlashPlate and solution-phase assays, respectively. The 5-benzamidoisoquinolin-1-ones were more selective for inhibition of PARP-2, whereas the 5-(ω-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC50(PARP-1)/IC50(PARP-2) = 9.3) to date, in a comparative study.