title: 5-Benzamidoisoquinolin-1-ones and 5-(ω-carboxyalkyl)isoquinolin-1-ones as isoform-selective inhibitors of poly(ADP-ribose) polymerase 2 (PARP-2).
abstract: 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═CHCO(2)H 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 (IC(50(PARP-1))/IC(50(PARP-2)) = 9.3) to date, in a comparative study.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sunderland
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Woon
authors.forename: Archana
authors.initials: A
authors.lastname: Dhami
authors.forename: Aoife B
authors.initials: AB
authors.lastname: Bergin
authors.forename: Mary F
authors.initials: MF
authors.lastname: Mahon
authors.forename: Pauline J
authors.initials: PJ
authors.lastname: Wood
authors.forename: Louise A
authors.initials: LA
authors.lastname: Jones
authors.forename: Sophie R
authors.initials: SR
authors.lastname: Tully
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.forename: Hashim
authors.initials: H
authors.lastname: Javaid
authors.forename: Niall M B
authors.initials: NM
authors.lastname: Martin
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006860:Hydrogen Bonding; D020128:Inhibitory Concentration 50; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007769:Lactams / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D010100:Oxygen / Q000737:chemistry; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000737:chemistry; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D007546:Isoquinolines; D007769:Lactams; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C483041:PARP2 protein, human; D011065:Poly(ADP-ribose) Polymerases; C039109:isoquinoline; D010100:Oxygen