A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides.
A new method for rapidly generating inhibitors of glyoxalase I inside tumor cells using S-(N-aryl-N-hydroxycarbamoyl)ethylsulfoxides.
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一种使用 S-(N-芳基-N-羟基氨基甲酰基)乙基亚砜在肿瘤细胞内快速生成乙二醛酶 I 抑制剂的新方法。
DOI：
10.1021/jm980712o
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发表时间：
1999
期刊：
影响因子：
--
通讯作者：
Creighton,DJ
中科院分区：
文献类型：
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作者：
Hamilton,DS;Kavarana,MJ;Sharkey,EM;Eiseman,JL;Creighton,DJ
烯二醇类似物-（n -对氯苯- n -羟基氨基氨酰基）谷胱甘肽是一种基于强大机制的抗癌靶酶乙草醛酶i的竞争性抑制剂。然而，这种化合物在体外对肿瘤细胞表现出有限的毒性，因为它不易扩散穿过细胞膜。我们描述了一种有效的方法，通过细胞内谷胱甘肽和细胞渗透性前药-（n -对氯苯- n -羟基氨基甲酰）乙基亚砜之间的酰基交换，间接将酶抑制剂递送到小鼠白血病L1210细胞中。无细胞体系中酰基交换反应的二级速率常数为1.84 mM-1min-1（100 mM磷酸钾缓冲液，5%乙醇，pH 7.5, 25°C）。与亚砜体外培养L1210细胞后，细胞内乙草醛酶I抑制剂浓度（kapp= 1.41±0.03 min-1(37°C)）迅速升高，细胞生长受到抑制（GI50= 0.5±0.1 μM）。与二烷基酯前药策略相比，这代表了效率和效力的改进，在二烷基酯前药策略中，抑制剂作为[甘酰基，谷氨酰]二乙基或双环戊基酯间接递送到肿瘤细胞中。π-谷胱甘肽转移酶能催化谷胱甘肽与亚砜之间的酰基交换反应，这表明亚砜或相关化合物可能对过表达该转移酶的肿瘤细胞表现出更大的选择性毒性。
The enediol analogueS-(N-p-chlorophenyl-N-hydroxycarbamoyl)glutathione is a powerful mechanism-based competitive inhibitor of the anticancer target enzyme glyoxalase I. Nevertheless, this compound exhibits limited toxicity toward tumor cells in vitro because it does not readily diffuse across cell membranes. We describe an efficient method for indirectly delivering the enzyme inhibitor into murine leukemia L1210 cells via acyl interchange between intracellular glutathione and the cell-permeable prodrugS-(N-p-chlorophenyl-N-hydroxycarbamoyl)ethylsulfoxide. The second-order rate constant for the acyl-interchange reaction in a cell-free system is 1.84 mM-1min-1(100 mM potassium phosphate buffer, 5% ethanol, pH 7.5, 25 °C). Incubation of L1210 cells with the sulfoxide in vitro results in a rapid increase in the intracellular concentration of the glyoxalase I inhibitor (kapp= 1.41 ± 0.03 min-1(37 °C)) and inhibition of cell growth (GI50= 0.5 ± 0.1 μM). This represents an improvement in both efficiency and potency over the dialkyl ester prodrug strategy in which the inhibitor is indirectly delivered into tumor cells as the [glycyl,glutamyl] diethyl or dicyclopentyl esters. The fact that π-glutathione transferase catalyzes the acyl-interchange reaction between GSH and the sulfoxide suggests that the sulfoxide, or related compounds, might exhibit greater selective toxicity toward tumor cells that overexpress the transferase.