Dinkova-Kostova A T, Massiah M A, Bozak R E, Hicks R J, Talalay P
Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Proc Natl Acad Sci U S A. 2001 Mar 13;98(6):3404-9. doi: 10.1073/pnas.051632198.
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.
诱导Ⅱ相酶和提高谷胱甘肽水平是保护哺乳动物及其细胞免受亲电试剂和活性氧的毒性及致癌作用影响的主要且充分的策略。诱导剂属于九种化学类别，除了通过氧化、还原或烷基化修饰巯基的能力外，几乎没有共同特性。大量证据表明，识别诱导剂并发出Ⅱ相基因转录增强信号的细胞“传感器”分子是凭借独特且高反应性的巯基功能来实现的，这些功能可识别诱导剂并与之发生共价反应。亚苄基链烷酮和亚苄基环烷酮是迈克尔反应受体，其诱导活性会因芳环上邻位（而非其他位置）存在羟基取代基而显著增强。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。质子核磁共振光谱未提供证据表明羟基化诱导剂上的β-乙烯基碳（推测的亲核攻击位点）的亲电性增加。令人惊讶的是，这些邻位羟基倾向于形成广泛的分子间氢键，这可能会提高反应性并促进硫醇的加成，从而提高诱导活性。
