SYNTHESIS OF 3-SUBSTITUTED BENZAMIDES AND 5-SUBSTITUTED ISOQUINOLIN-1(2H)-ONES AND PRELIMINARY EVALUATION AS INHIBITORS OF POLY(ADP-RIBOSE)POLYMERASE (PARP)

Inhibitors of poly(ADP-ribose)polymerase (PARP) inhibit repair of dama ged 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-(bro moacetyl)benzamide, followed by treatment with base, gave RS-3-oxirany lbenzamide. Reduction of 3-(hydroxyacetyl)benzonitrile with bakers' ye ast gave 'the R-diol which was converted to R-3-(1,2-dihydroxyethyl)be nzamide. Similar reduction of 3-(acetoxyacetyl)benzonitrile led toward s the S-diol which was converted to its cyclic acetonide. E-2-(2,6-Dic yanophenyl)-N,N-dimethylethenamine was formed by condensation of 2,6-d icyanotoluene with dimethylformamide dimethyl acetal (DMFDMA); cyclisa tion under acidic conditions afforded 5-cyanoisoquinolin-1-one. Heck c oupling of 5-iodoisoquinolin-1-one with propenoic acid formed E-3-(1-o xoisoquinolin-5-yl)propenoic acid. 3-Oxiranylbenzamide, 5-bromoisoquin olin-1-one and 5-iodoisoquinolin-1-one were among the most potent inhi bitors of PARP activity in a preliminary screen in vitro. (C) 1998 Els evier Science Ltd, All rights reserved.