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

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• 作者：Peter T. Sunderland ; Esther C. Y. Woon ; Archana Dhami ; Aoife B. Bergin ; Mary F. Mahon ; Pauline J. Wood ; Louise A. Jones ; Sophie R. Tully ; Matthew D. Lloyd ; Andrew S. Thompson ; Hashim Javaid ; Niall M. B. Martin ; Michael D. Threadgill
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：April 14, 2011
• 年：2011
• 卷：54
• 期：7
• 页码：2049-2059
• 全文大小：1007K
• 年卷期：v.54,no.7(April 14, 2011)
• ISSN：1520-4804

文摘

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鈺怌HCO₂H 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-(蠅-carboxyalkyl)isoquinolin-1-ones were less so. 5-Benzamidoisoquinolin-1-one is the most PARP-2-selective compound (IC_50(PARP-1)/IC_50(PARP-2) = 9.3) to date, in a comparative study.