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

Overview

Journal J Med Chem

Publisher American Chemical Society

Specialty Chemistry

Date 2011 Sep 30

PMID 21955333

Citations 21

Authors

Rui Zhu

Mao-Chin Liu

Mei-Zhen Luo

Philip G Penketh

Raymond P Baumann

Krishnamurthy Shyam

Alan C Sartorelli

Affiliations

Soon will be listed here.

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.

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