title: 4-nitrobenzyloxycarbonyl derivatives of O(6)-benzylguanine as hypoxia-activated prodrug inhibitors of O(6)-alkylguanine-DNA alkyltransferase (AGT), which produces resistance to agents targeting the O-6 position of DNA guanine.
abstract: A series of 4-nitrobenzyloxycarbonyl prodrug derivatives of O(6)-benzylguanine (O(6)-BG), conceived as prodrugs of O(6)-BG, an inhibitor of the resistance protein O(6)-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 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.
authors.affiliation: Department of Pharmacology and Developmental Therapeutics Program, Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8066, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Zhu
authors.forename: Mao-Chin
authors.initials: MC
authors.lastname: Liu
authors.forename: Mei-Zhen
authors.initials: MZ
authors.lastname: Luo
authors.forename: Philip G
authors.initials: PG
authors.lastname: Penketh
authors.forename: Raymond P
authors.initials: RP
authors.lastname: Baumann
authors.forename: Krishnamurthy
authors.initials: K
authors.lastname: Shyam
authors.forename: Alan C
authors.initials: AC
authors.lastname: Sartorelli
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D051379:Mice; D009251:NADPH-Ferrihemoprotein Reductase / Q000737:chemistry; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000737:chemistry
chemical_list: D018906:Antineoplastic Agents, Alkylating; D006834:Hydrazines; D011355:Prodrugs; D013449:Sulfonamides; C064976:O(6)-benzylguanine; C483604:laromustine; D006147:Guanine; D004247:DNA; D014969:Xanthine Oxidase; D009251:NADPH-Ferrihemoprotein Reductase; D019853:O(6)-Methylguanine-DNA Methyltransferase