Potency of Michael reaction accepters as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups
Potency of Michael reaction accepters as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups
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DOI：
10.1073/pnas.051632198
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发表时间：
2001-03-13
影响因子：
11.1
通讯作者：
Talalay, P
中科院分区：
文献类型：
--
作者：
Dinkova-Kostova, AT;Massiah, MA;Talalay, P
2期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活性氧的毒性和致癌作用的主要和充分的策略。诱导剂属于九个化学类别，除了能够通过氧化，还原或烷基化修饰巯基外，几乎没有共同的性质。许多证据表明，细胞“传感器”分子能够识别诱导剂，并通过独特的高活性巯基功能识别诱导剂并与之共价反应，从而向2期基因的增强转录发出信号。苄基烷酮和环烷酮是迈克尔反应受体，其诱导剂效力因芳香环上的邻羟基取代基（而不是其他）的存在而大大增加。这种增强与邻羟基化衍生物与模型巯基化合物的快速反应性有关。质子核磁共振波谱没有证据表明羟基化诱导剂上的对乙烯基碳（假定的亲核攻击位点）的亲电性增加。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，这可能提高反应性，促进硫醇的加入，从而提高诱导剂的效价。
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 accepters 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 P-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.