期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 21, 页码 7720-7728出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm201115f
关键词
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资金
- U.S. Public Health Service
- National Cancer Institute [CA090671, CA122112, CA129186]
- National Foundation for Cancer Research
A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O-6-benzylguanine (O-6-BG), conceived as pro-drugs of O-6-BG, an inhibitor of the resistance protein O-6-alkylguanine-DNA alkyltransferase (ACT), were synthesized and evaluated for their ability to undergo bioreductive activation by reductase enzymes under oxygen deficiency. Three agents of this class, 4-nitrobenzyl (6-(benzyloxy)-9H-purin-2-yl)carbamate (1) and its monomethyl (2) and gem-dimethyl analogues (3), were tested for activation by reductase enzyme systems under oxygen deficient conditions. Compound 3, the most water-soluble of these agents, gave the highest yield of O-6-BG following reduction of the nitro group trigger. Compound 3 was also evaluated for its ability to sensitize 1,2-bis(methylsulfonyl)-1-(2-chloroethyl)-2-[(methylamino)carbonyl]hydrazine (laromustine)-resistant DU145 human prostate carcinoma cells, which express high levels of AGT, to the cytotoxic effects of this agent under normoxic and oxygen deficient conditions. While 3 had little or no effect on laromustine cytotoxicity under aerobic conditions, significant enhancement occurred under oxygen deficiency, providing evidence for the preferential release of the AGT inhibitor O-6-BG under hypoxia.
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