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Resistance-modifying agents. 5.1 Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP)

Lookup NU author(s): Professor Roger Griffin, Professor Alan Calvert, Professor Nicola Curtin, Professor Herbie Newell, Professor Bernard Golding

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Abstract

Clinical studies concerning the role of poly(ADP-ribose) polymerase (PARP) in the repair of drug- and radiation-induced DNA damage have been impeded by the poor solubility, lack of potency, and limited specificity of currently available inhibitors. A series of 2-alkyl- and 2-aryl-substituted 8-hydroxy-, 8-methoxy-, and 8-methylquinazolin-4(3H)-ones has been synthesized and evaluated for PARP inhibitory activity in permeabilized L1210 murine leukemia cells. 8-Methoxy- and 8-methylquinazolinones (14-34) were readily prepared by acylation of 3-substituted anthranilamides with the appropriate acid chloride, followed by base-catalyzed cyclization. The requisite 8-hydroxyquinazolinones (6, 35-39) were synthesized by demethylation of the corresponding 8-methoxyquinazolinones with BBr3. N- Methylation of 8-methoxy-2-methylquinazolinone (15) with MeI, followed by O- demethylation by BBr3, afforded the control N3-methylquinazolinones 42 and 43, respectively. In general, an 8-hydroxy or 8-methyl substituent enhanced inhibitory activity in comparison with an 8-methoxy group. 2- Phenylquinazolinones were marginally less potent than the corresponding 2- methylquinazolinones, but the introduction of an electron-withdrawing or electron-donating 4'-substituent on the 2-aryl ring invariably increased potency. This was particularly evident in the 8-methylquinazolinone series (IC50 values 0.13-0.27 μM), which are among the most potent PARP inhibitors reported to date. N3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 μM). In studies with L1210 cells in vitro, a concentration of 200 μM 8=hydroxy-2- methylquinazolinone (6, NU1025) (IC50 value 0.40 μM) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole- 4-carboxamide and 7-radiation 3.5 and 1.4-fold, respectively, at the 10% survival level.


Publication metadata

Author(s): Griffin, R. J., Srinivasan, S., Bowman, K., Calvert, A. H., Curtin, N. J., Newell, D. R., Pemberton, L. C., Golding, B. T.

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 1998

Volume: 41

Issue: 26

Pages: 5247-5256

Print publication date: 17/12/1998

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

URL: http://dx.doi.org/10.1021/jm980273t

DOI: 10.1021/jm980273t

PubMed id: 9857092


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