Synthesis of 3-substituted benzamides and 5-substituted isoquinolin-1(2H)-ones and preliminary evaluation as inhibitors of poly(ADP-ribose)polymerase (PARP)

Bioorg Med Chem. 1998 Jun;6(6):721-34. doi: 10.1016/s0968-0896(98)00029-7.

Abstract

Inhibitors of poly(ADP-ribose)polymerase (PARP) inhibit repair of damaged DNA and thus potentiate radiotherapy and chemotherapy of cancer. 3-Substituted benzamides and 5-substituted isoquinolin-1-ones have been synthesised and evaluated for inhibition of PARP. Reduction of 3-(bromoacetyl)benzamide, followed by treatment with base, gave RS-3-oxiranylbenzamide. Reduction of 3-(hydroxyacetyl)benzonitrile with bakers' yeast gave the R-diol which was converted to R-3-(1,2-dihydroxyethyl)benzamide. Similar reduction of 3-(acetoxyacetyl)benzonitrile led towards the S-diol which was converted to its cyclic acetonide. E-2-(2,6-Dicyanophenyl)-N,N-dimethylethenamine was formed by condensation of 2,6-dicyanotoluene with dimethylformamide dimethyl acetal (DMFDMA); cyclisation under acidic conditions afforded 5-cyanoisoquinolin-1-one. Heck coupling of 5-iodoisoquinolin-1-one with propenoic acid formed E-3-(1-oxoisoquinolin-5-yl)propenoic acid. 3-Oxiranylbenzamide, 5-bromoisoquinolin-1-one and 5-iodoisoquinolin-1-one were among the most potent inhibitors of PARP activity in a preliminary screen in vitro.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Cell Line
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Isoquinolines / chemical synthesis*
  • Isoquinolines / chemistry
  • Isoquinolines / pharmacology
  • Mice
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Structure-Activity Relationship

Substances

  • 3-oxiranylbenzamide
  • 5-bromoisoquinolin-1-one
  • 5-iodoisoquinolin-1-one
  • Benzamides
  • Enzyme Inhibitors
  • Isoquinolines
  • Poly(ADP-ribose) Polymerase Inhibitors