Document Detail

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.
MedLine Citation:
PMID:  21955333     Owner:  NLM     Status:  MEDLINE    
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.
Rui Zhu; Mao-Chin Liu; Mei-Zhen Luo; Philip G Penketh; Raymond P Baumann; Krishnamurthy Shyam; Alan C Sartorelli
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-10-17
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  54     ISSN:  1520-4804     ISO Abbreviation:  J. Med. Chem.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-11-03     Completed Date:  2012-02-07     Revised Date:  2014-09-12    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  7720-8     Citation Subset:  IM    
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MeSH Terms
Antineoplastic Agents, Alkylating / chemical synthesis*,  chemistry,  pharmacology
Cell Hypoxia
Cell Line, Tumor
DNA / metabolism*
Drug Resistance, Neoplasm
Drug Screening Assays, Antitumor
Drug Synergism
Guanine / analogs & derivatives*,  chemical synthesis,  chemistry,  pharmacology
Hydrazines / pharmacology
NADPH-Ferrihemoprotein Reductase / chemistry
O(6)-Methylguanine-DNA Methyltransferase / antagonists & inhibitors*
Prodrugs / chemical synthesis*,  chemistry,  pharmacology
Structure-Activity Relationship
Sulfonamides / pharmacology
Xanthine Oxidase / chemistry
Grant Support
CA090671/CA/NCI NIH HHS; CA122112/CA/NCI NIH HHS; CA129186/CA/NCI NIH HHS; R01 CA090671/CA/NCI NIH HHS; R01 CA090671-08/CA/NCI NIH HHS; R01 CA122112/CA/NCI NIH HHS; R01 CA122112-06/CA/NCI NIH HHS
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Hydrazines; 0/Prodrugs; 0/Sulfonamides; 173424-77-6/laromustine; 19916-73-5/O(6)-benzylguanine; 5Z93L87A1R/Guanine; 9007-49-2/DNA; EC Oxidase; EC Reductase; EC Methyltransferase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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