title: One-pot tandem Hurtley-retro-Claisen-cyclisation reactions in the synthesis of 3-substituted analogues of 5-aminoisoquinolin-1-one (5-AIQ), a water-soluble inhibitor of PARPs.
abstract: Poly(ADP-ribose)polymerase-1 (PARP-1) is an important target for drug design for several therapeutic applications. 5-Aminoisoquinolin-1-one (5-AIQ) is a highly water-soluble lead compound; synthetic routes to 3-substituted analogues were explored. Tandem Hurtley coupling of β-diketones with 2-bromo-3-nitrobenzoic acid, retro-Claisen acyl cleavage and cyclisation gave the corresponding 3-substituted 5-nitroisocoumarins. Treatment with ammonia at high temperature and reduction with tin(II) chloride gave eleven target 3-substituted 5-AIQs, which were all soluble in water (>1% w/v) as their HCl salts. Most were more potent than 5-AIQ as inhibitors of PARP-1 and of PARP-2 in vitro, the most active being 5-amino-3-methylisoquinolin-1-one (PARP-1: IC50=0.23μM vs IC50=1.6μM for 5-AIQ). Some rationalisation of the SAR was achieved through molecular modelling.
authors.affiliation: Medicinal Chemistry, Department of Pharmacy & Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
authors.forename: Esther C Y
authors.initials: EC
authors.lastname: Woon
authors.forename: Peter T
authors.initials: PT
authors.lastname: Sunderland
authors.forename: Helen A
authors.initials: HA
authors.lastname: Paine
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Lloyd
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Thompson
authors.forename: Michael D
authors.initials: MD
authors.lastname: Threadgill
mesh_terms: D000818:Animals; D001665:Binding Sites; D002645:Chickens; D003500:Cyclization; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006860:Hydrogen Bonding; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry*; D062105:Molecular Docking Simulation; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D014867:Water / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D007546:Isoquinolines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D014867:Water; D011065:Poly(ADP-ribose) Polymerases
keywords: Hurtley reaction; Isocoumarin; Isoquinolin-1-one; PARP-1; Tandem