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.
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.
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DOI：
10.1021/jm201115f
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发表时间：
2011-11-10
影响因子：
7.3
通讯作者：
Sartorelli, Alan C.
中科院分区：
文献类型：
--
作者：
Zhu, Rui;Liu, Mao-Chin;Luo, Mei-Zhen;Penketh, Philip G.;Baumann, Raymond P.;Shyam, Krishnamurthy;Sartorelli, Alan C.
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.
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影响因子：
5.8
作者：
Baumann, Raymond P.;Penketh, Philip G.;Ishiguro, Kimiko;Shyam, Krishnamurthy;Zhu, Yong L.;Sartorelli, Alan C.
通讯作者：
Sartorelli, Alan C.
影响因子：
5.7
作者：
Ishiguro, K;Shyam, K;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
3.4
作者：
Baumann RP;Penketh PG;Seow HA;Shyam K;Sartorelli AC
通讯作者：
Sartorelli AC
影响因子：
3.1
作者：
Baumann, RP;Seow, HA;Sartorelli, AC
通讯作者：
Sartorelli, AC
影响因子：
3
作者：
Baumann, RP;Shyam, K;Sartorelli, AC
通讯作者：
Sartorelli, AC