Synthesis of 4-alkyl-, 4-aryl- and 4-arylamino-5-aminoisoquinolin-1-ones and identification of a new PARP-2 selective inhibitor

Org Biomol Chem. 2011 Feb 7;9(3):881-91. doi: 10.1039/c0ob00665c. Epub 2010 Dec 2.

Abstract

The considerable interest in substituted isoquinolin-1-ones related to 5-aminoisoquinolin-1-one (5-AIQ) as drugs points to a need for an efficient and straightforward synthesis of the 4,5-disubstituted bicycles. Bromination of 5-nitroisoquinolin-1-one gave 4-bromo-5-nitroisoquinolin-1-one but neither this nor 5-amino-4-bromoisoquinolin-1-one would participate in Pd-catalysed couplings. Protection of the lactam as 1-methoxy- and 1-benzyloxy-4-bromo-5-nitroisoquinolines, however, permitted Stille, Suzuki and Buchwald-Hartwig couplings to take place in high yields, insensitive to electronic demands and severe steric bulk in the arylboronic acids. Lithiation of 4-bromo-1-methoxy-5-nitroisoquinoline and quench with iodomethane gave 1-methoxy-4-methyl-5-nitroisoquinoline in low yield. Demethylation of the 1-methoxy-4-substituted-5-nitroisoquinolines with hydrogen bromide gave 4-substituted-5-nitroisoquinolin-1-ones, whereas hydrogenolytic debenzylation was achieved with simultaneous reduction of the 5-nitro group. 5-Amino-4-(4-trifluoromethylphenyl)isoquinolin-1-one was identified as a new potent and selective inhibitor of poly(ADP-ribose)polymerase-2 (PARP-2).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkylation
  • Amines / chemistry*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / pharmacology
  • Models, Molecular
  • Molecular Structure
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Structure-Activity Relationship

Substances

  • Amines
  • Enzyme Inhibitors
  • Isoquinolines
  • Poly(ADP-ribose) Polymerase Inhibitors
  • isoquinoline