Lookup NU author(s): Professor Roger Griffin,
Professor Alan Calvert,
Professor Nicola Curtin,
Professor Herbie Newell,
Professor Bernard Golding
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
Two novel series of inhibitors of the DNA repair enzyme poly(ADP-ribose)polymerase (PARP) were synthesized and evaluated for biological activity. In the benzimidazole-4-carboxamide series, the carbamoyl function was restricted into the putative biologically active conformation via an intramolecular hydrogen bond, while for quinazolin-4-[3H]-ones this was achieved by incorporation of the group into a heterocyclic ring. For both series of compounds, syntheses involved acylation of substituted anthranilic acid derivatives, followed by acid- or base-catalysed cyclization. 8-Hydroxyquinazolin-4-[3H]-ones were prepared from the corresponding 8-methoxy compounds by dealkylation with boron tribromide. PARP inhibitory activity was determined in permeabilized L1210 murine leukaemia cells, in comparison with the established inhibitor 3-hydroxybenzamide (IC50 = 8.3 μM). For both series, inhibitory activity varied with the nature of the 2-substituent, with benzimidazole-4-carboxamides proving approximately tenfold more potent than the previously prepared benzoxazole-4-carboxamides. 2-Arylbenzimidazoles were especially active, and 2-(4-methoxyphenyl)benzimidazole-4-carboxamide (IC50 = 60 nM) is the most potent PARP inhibitor reported to date. In the quinazolinone series, a 2-(4-nitrophenyl) substituent, and either an 8-methyl or 8-hydroxy group conferred potent inhibitory activity, with IC50 values of 0.13 and 0.23 μM, respectively, being observed.
Author(s): Griffin, R.J., Srinivasan, S., White, A.W., Bowman, K., Calvert, A.H., Curtin, N.J., Newell, D.R., Golding, B.T.
Publication type: Article
Publication status: Published
Journal: Pharmaceutical Sciences
Print publication date: 01/01/1996
ISSN (print): 1356-6881