Inhibition of ribonucleotide reductase by antitumor agents related to levodopa and dopamine.
Inhibition of ribonucleotide reductase by antitumor agents related to levodopa and dopamine.
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与左旋多巴和多巴胺相关的抗肿瘤药物对核糖核苷酸还原酶的抑制。
DOI：
10.1016/0006-2952(85)90043-7
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发表时间：
1985
影响因子：
5.8
通讯作者：
Wick,MM
中科院分区：
文献类型：
--
作者：
FitzGerald,GB;Wick,MM
使用从L1210细胞中部分纯化的酶，结构上与多巴胺相关的二羟基苯衍生物被证明可逆地失活核糖核苷酸还原酶。结构活性分析表明，含有带负电荷基团的侧链衍生物的抑制活性显著降低。这些化合物抑制核糖核苷酸还原酶的能力依赖于邻位羟基，与自由基抑制活性无关。用Lineweaver-Burk方法进行动力学分析表明，3，4-二羟基苄胺对核糖核苷酸还原酶的抑制作用与还原底物二硫代赤藓糖醇具有竞争性。这种类似物与羟基脲结合，产生协同抑制或核糖核苷酸还原酶，提示不同的作用部位。使用吐温80处理的L1210细胞，发现这些药物对完整的可逆通透性细胞中的核糖核苷酸还原酶活性有立即抑制作用。此外，尽管这些药物对DNA聚合酶没有立竿见影的效果，但在通透性的L1210细胞中(当细胞与二酚衍生物预先孵育1小时后再稳定)，DNA聚合酶活性明显受到抑制。DNA合成的两个关键酶似乎依次被这些类似物抑制，还原形式(苯二酚)抑制核苷酸还原酶，氧化形式(苯醌)抑制DNA聚合酶。
Using partially purified enzyme from L1210 cells, dihydroxybenzene derivatives related structurally to dopamine were shown to reversibly inactivate ribonucleotide reductase. A structureactivity analysis revealed that derivatives with side-chains, which contain a negatively-charged group, had significantly reduced inhibitory activity. The ability of these compounds to inhibit ribonucleotide reductase was dependent on the hydroxyl groups being in the ortho position and did not correlate with free radical inhibitory activity. A kinetic analysis by the method of Lineweaver-Burk indicated that the inhibition of ribonucleotide reductase by the derivative 3,4-dihydroxybenzylamine was competitive with the reducing substrate dithioerythritol. This analog, in combination with hydroxyurea, gave synergistic inhibition or ribonucleotide reductase, suggesting different sites of action. Using Tween 80-treated L1210 cells, it was found that these drugs had an immediate inhibitory effect on ribonucleotide reductase activity in intact, reversibly permeabilized cells. Furthermore, although these drugs had no immediate effect on DNA polymerase, in permeabilized L1210 cells (when the cells were preincubated with the dihydroxybenzene derivatives for 1 hr prior to penneabilization), there was significant inhibition of DNA polymerase activity. The two key enzymes for DNA synthesis appear to be sequentially inhibited by these analogs, with the reduced form (quinol) inhibiting ribonucleotide reductase and the oxidized form (quinone) inhibiting DNA polymerase.