Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selective antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide.
Isotopic labeling experiments that elucidate the mechanism of DNA strand cleavage by the hypoxia-selective antitumor agent 1,2,4-benzotriazine 1,4-di-N-oxide.
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DOI：
10.1021/tx400356y
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发表时间：
2014-01-21
影响因子：
4.1
通讯作者：
Gates KS
中科院分区：
文献类型：
--
作者：
Shen X;Rajapakse A;Gallazzi F;Junnotula V;Fuchs-Knotts T;Glaser R;Gates KS
1，2，4-苯并三嗪1，4-二氧化物是一类重要的潜在抗癌药物，可选择性杀死实体瘤中发现的低氧（缺氧）细胞。这些化合物经历细胞内单电子酶促还原以产生氧敏感性药物自由基中间体，其在缺氧条件下向前分配以产生引起细胞杀伤DNA损伤的高反应性二级自由基。在这里，我们的特点是生物还原激活，缺氧选择性DNA链裂解的1，2，4-苯并三嗪1，4-二氧化物。我们发现，在缺氧条件下，在氘原子供体甲醇-d4的存在下，1，2，4-苯并三嗪1，4-二氧化物的单电子酶促激活产生非氘代单N-氧化物代谢物。这和其他同位素标记研究的结果提供了反对原子抽象药物自由基中间体的产生的证据，并与涉及从酶激活的1，2，4-苯并三嗪1，4-二氧化物中释放羟基自由基的DNA损伤机制一致。
The 1,2,4-benzotriazine 1,4-dioxides are an important class of potential anticancer drugs that selectively kill the low-oxygen (hypoxic) cells found in solid tumors. These compounds undergo intracellular one-electron enzymatic reduction to yield an oxygen-sensitive drug radical intermediate that partitions forward, under hypoxic conditions, to generate a highly reactive secondary radical that causes cell killing DNA damage. Here we characterized bioreductively-activated, hypoxia-selective DNA-strand cleavage by 1,2,4-benzotriazine 1,4-dioxide. We found that one-electron enzymatic activation of 1,2,4-benzotriazine 1,4-dioxide under hypoxic conditions in the presence of the deuterium atom donor methanol-d4 produced non-deuterated mono-N-oxide metabolites. This and the results of other isotopic labeling studies provided evidence against the generation of atom-abstracting drug radical intermediates and are consistent with a DNA-damage mechanism involving release of hydroxyl radical from enzymatically-activated 1,2,4-benzotriazine 1,4-dioxides.
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影响因子：
15
作者：
Birincioglu, M;Jaruga, P;Gates, KS
通讯作者：
Gates, KS
影响因子：
3.2
作者：
Anderson, RF;Shinde, SS;Denny, WA
通讯作者：
Denny, WA
影响因子：
11.2
作者：
Evans, James W.;Chernikova, Sophia B.;Brown, J. Martin
通讯作者：
Brown, J. Martin
影响因子：
4.1
作者：
Daniels, JS;Gates, KS;Greenberg, MM
通讯作者：
Greenberg, MM
影响因子：
15
作者：
Chowdhury, Goutam;Junnotula, Venkatraman;Gates, Kent S.
通讯作者：
Gates, Kent S.