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1.  4-Nitrobenzyloxycarbonyl Derivatives of O6-Benzylguanine as Hypoxia-Activated Prodrug Inhibitors of O6-Alkylguanine-DNA Alkyltransferase (AGT) which Produces Resistance to Agents Targeting the O-6 Position of DNA Guanine 
Journal of medicinal chemistry  2011;54(21):7720-7728.
A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O6-benzylguanine (O6-BG), conceived as prodrugs of O6-BG, an inhibitor of the resistance protein O6-alkylguanine-DNA alkyltransferase (AGT), 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 O6-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 O6-BG under hypoxia.
PMCID: PMC3220054  PMID: 21955333
O6-benzylguanine; O6-alkylguanine-DNA alkyltransferase; laromustine; KS119; 1,2-bis(sulfonyl)hydrazines; oxygen deficiency
2.  Structure and Function Converge To Identify a Hydrogen Bond in a Group I Ribozyme Active Site** 
PMCID: PMC2862986  PMID: 19708048
atomic substitution; enzyme catalysis; group I introns; ribozymes; structure–function relationships

Results 1-2 (2)