Resistance-modifying agents. 5. Synthesis and biological properties of quinazolinone inhibitors of the DNA repair enzyme poly(ADP-ribose) polymerase (PARP).
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.
Griffin
R J
RJ
Department of Chemistry, Bedson Building, The University, Newcastle upon Tyne NE1 7RU, U.K.
Srinivasan
S
S
Bowman
K
K
Calvert
A H
AH
Curtin
N J
NJ
Newell
D R
DR
Pemberton
L C
LC
Golding
B T
BT
D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D004260:DNA Repair; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005720:Gamma Rays; D007939:Leukemia L1210 / Q000473:pathology; D051379:Mice; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; C115774:NU 1025; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011799:Quinazolines; D003606:Dacarbazine; C010243:5-(3-methyl-1-triazeno)imidazole-4-carboxamide