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Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP).
J Med Chem. 1998 Dec 17; 41(26):5247-56.JM

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 microM), which are among the most potent PARP inhibitors reported to date. N3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 microM). In studies with L1210 cells in vitro, a concentration of 200 microM 8-hydroxy-2-methylquinazolinone (6, NU1025) (IC50 value 0.40 microM) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide and gamma-radiation 3.5- and 1.4-fold, respectively, at the 10% survival level.

Authors+Show Affiliations

Griffin RJ
Department of Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, U.K.
Srinivasan S
No affiliation info available
Bowman K
No affiliation info available
Calvert AH
No affiliation info available
Curtin NJ
No affiliation info available
Newell DR
No affiliation info available
Pemberton LC
No affiliation info available
Golding BT
No affiliation info available

MeSH

Alkylating AgentsAnimalsAntineoplastic AgentsCell SurvivalDNA RepairDacarbazineDrug Resistance, NeoplasmDrug Screening Assays, AntitumorDrug SynergismEnzyme InhibitorsGamma RaysLeukemia L1210MicePoly(ADP-ribose) Polymerase InhibitorsQuinazolinesStructure-Activity RelationshipTumor Cells, Cultured

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9857092

Citation

Griffin, R J., et al. "Resistance-modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme poly(ADP-ribose) Polymerase (PARP)." Journal of Medicinal Chemistry, vol. 41, no. 26, 1998, pp. 5247-56.
Griffin RJ, Srinivasan S, Bowman K, et al. Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). J Med Chem. 1998;41(26):5247-56.
Griffin, R. J., Srinivasan, S., Bowman, K., Calvert, A. H., Curtin, N. J., Newell, D. R., Pemberton, L. C., & Golding, B. T. (1998). Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). Journal of Medicinal Chemistry, 41(26), 5247-56.
Griffin RJ, et al. Resistance-modifying Agents. 5. Synthesis and Biological Properties of Quinazolinone Inhibitors of the DNA Repair Enzyme poly(ADP-ribose) Polymerase (PARP). J Med Chem. 1998 Dec 17;41(26):5247-56. PubMed PMID: 9857092.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP). AU - Griffin,R J, AU - Srinivasan,S, AU - Bowman,K, AU - Calvert,A H, AU - Curtin,N J, AU - Newell,D R, AU - Pemberton,L C, AU - Golding,B T, PY - 1998/12/19/pubmed PY - 1998/12/19/medline PY - 1998/12/19/entrez SP - 5247 EP - 56 JF - Journal of medicinal chemistry JO - J Med Chem VL - 41 IS - 26 N2 - 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 microM), which are among the most potent PARP inhibitors reported to date. N3-Methylquinazolinones 42 and 43 were essentially devoid of activity (IC50 values > 100 microM). In studies with L1210 cells in vitro, a concentration of 200 microM 8-hydroxy-2-methylquinazolinone (6, NU1025) (IC50 value 0.40 microM) potentiated the cytotoxicity of the monomethylating agent 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide and gamma-radiation 3.5- and 1.4-fold, respectively, at the 10% survival level. SN - 0022-2623 UR - https://www.unboundmedicine.com/medline/citation/9857092/Resistance_modifying_agents__5__Synthesis_and_biological_properties_of_quinazolinone_inhibitors_of_the_DNA_repair_enzyme_poly_ADP_ribose__polymerase__PARP__ L2 - https://doi.org/10.1021/jm980273t DB - PRIME DP - Unbound Medicine ER -