Bioreductive activation of a series of indolequinones by human DT-diaphorase: Structure-activity relationships
Bioreductive activation of a series of indolequinones by human DT-diaphorase: Structure-activity relationships
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DOI：
10.1021/jm991063z
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发表时间：
1999-10-07
影响因子：
7.3
通讯作者：
Stratford, IJ
中科院分区：
文献类型：
--
作者：
Phillips, RM;Naylor, MA;Stratford, IJ
研究了一系列吲哚醌类化合物，包括带有不同官能团的EO 9衍生物和相关的吲哚-2-甲酰胺，以期鉴定赋予纯化的人NAD（P）H：醌氧化还原酶（DT-黄递酶）底物特异性、对DNA损伤物种的生物还原活化以及对富含DT-黄递酶的细胞的体外选择性的分子特征。存在广谱的底物特异性，但吲哚醌核的微小变化对底物特异性有显著影响。在2位的修饰在底物特异性方面是有利的，因为这些位置位于结合位点入口处，如通过分子建模研究所确定的。相比之下，在（吲哚-3-基）甲基位置上用大体积离去基团或含有氯原子的基团取代产生作为不良底物的化合物，其中一些是CDDT-心肌黄酶。建模研究表明，这些基团靠近机械上重要的氨基酸Tyr 156和His 162，可能导致活性位点内的烷基化或电荷中继机制的破坏。在5位的氮丙啶基对于在有氧条件下对富含DT-心肌黄酶的细胞的效力和选择性是必不可少的。最有效的底物诱导的质量更大的单链DNA断裂，在无细胞测定通过氧化还原机制，涉及生产过氧化氢（过氧化氢酶可降解）。这种损伤不太可能形成它们在细胞中作用机制的主要部分，因为效力与DNA损伤的程度无关。在低氧选择性方面，在3位的修饰产生的化合物是DT-心肌黄酶的不良底物，但具有高的低氧细胞毒性比。
A series of indolequinones including derivatives of EO9 bearing various functional groups and related indole-2-carboxamides have been studied with a view to identifying molecular features which confer substrate specificity for purified human NAD(P)H:quinone oxidoreductase (DT-diaphorase), bioreductive activation to DNA-damaging species, and selectivity for DT-diaphorase-rich cells in vitro. A broad spectrum of substrate specificity exists, but minor changes to the indolequinone nucleus have a significant effect upon substrate specificity. Modifications at the 2-position are favorable in terms of substrate specificity as these positions are located at the binding site entrance as determined by molecular modeling studies. In contrast, substitutions at the (indol-3-yl)methyl position with bulky leaving groups or a group containing a chlorine atom result in compounds which are poor substrates, some of which inactivate DT-diaphorase. Modeling studies demonstrate that these groups sit close to the mechanistically important amino acids Tyr 156 and His 162 possibly resulting in either alkylation within the active site or disruption of charge-relay mechanisms. An aziridinyl group at the 5-position is essential for potency and selectivity to DT-diaphorase-rich cells under aerobic conditions. The most efficient substrates induced qualitatively greater single-strand DNA breaks in cell-free assays via a redox mechanism involving the production of hydrogen peroxide (catalase inhibitable). This damage is unlikely to form a major part of their mechanism of action in cells since potency does not correlate with extent of DNA damage. In terms of hypoxia selectivity, modifications at the 3-position generate compounds which are poor substrates for DT-diaphorase but have high hypoxic cytotoxicity ratios.