Induction of phase 2 enzymes and elevations of glutathione are major and sufficient strategies for protecting mammals and their cells against the toxic and carcinogenic effects of electrophiles and reactive forms of oxygen. Inducers belong to nine chemical classes and have few common properties except for their ability to modify sulfhydryl groups by oxidation, reduction, or alkylation. Much evidence suggests that the cellular "sensor" molecule that recognizes the inducers and signals the enhanced transcription of phase 2 genes does so by virtue of unique and highly reactive sulfhydryl functions that recognize and covalently react with the inducers. Benzylidene-alkanones and -cycloalkanones are Michael reaction acceptors whose inducer potency is profoundly increased by the presence of ortho- (but not other) hydroxyl substituent(s) on the aromatic ring(s). This enhancement correlates with more rapid reactivity of the ortho-hydroxylated derivatives with model sulfhydryl compounds. Proton NMR spectroscopy provides no evidence for increased electrophilicity of the beta-vinyl carbons (the presumed site of nucleophilic attack) on the hydroxylated inducers. Surprisingly, these ortho-hydroxyl groups display a propensity for extensive intermolecular hydrogen bond formation, which may raise the reactivity and facilitate addition of mercaptans, thereby raising inducer potencies.

译文

2相酶的诱导和谷胱甘肽的升高是保护哺乳动物及其细胞免受亲电试剂和反应性氧气的毒性和致癌作用的主要而充分的策略。诱导剂属于九种化学类别,除了具有通过氧化,还原或烷基化修饰巯基的能力外,几乎没有共同的性质。许多证据表明,识别诱导物并发出增强的2期基因转录信号的细胞 “传感器” 分子是通过识别诱导物并与诱导物共价反应的独特且高反应性的巯基功能实现的。亚苄基链烷酮和-环烷酮是迈克尔反应受体,其诱导剂效力因芳环上邻位 (而不是其他) 羟基取代基的存在而大大提高。这种增强与邻位羟基化衍生物与模型巯基化合物的更快反应性相关。质子NMR光谱没有提供增加 β-乙烯基碳 (假定的亲核攻击位点) 对羟基化诱导剂的亲电性的证据。令人惊讶的是,这些邻羟基显示出广泛的分子间氢键形成的倾向,这可能会提高反应性并促进硫醇的添加,从而提高诱导剂的效力。

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