Potency of Michael reaction acceptors as inducers of enzymes that protect against carcinogenesis depends on their reactivity with sulfhydryl groups.
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.
Dinkova-Kostova
A T
AT
Department of Pharmacology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
Massiah
M A
MA
Bozak
R E
RE
Hicks
R J
RJ
Talalay
P
P
D000818:Animals; D001597:Benzylidene Compounds / Q000737:chemistry / Q000378:metabolism*; D002074:Butanones / Q000737:chemistry / Q000378:metabolism; D006528:Carcinoma, Hepatocellular; D002599:Chalcone / Q000737:chemistry / Q000378:metabolism; D002934:Cinnamates / Q000737:chemistry / Q000378:metabolism; D003374:Coumarins / Q000737:chemistry / Q000378:metabolism; D003512:Cyclohexanones / Q000737:chemistry / Q000378:metabolism; D003517:Cyclopentanes / Q000737:chemistry / Q000378:metabolism; D004790:Enzyme Induction; D038181:FMN Reductase; D005978:Glutathione / Q000378:metabolism; D005982:Glutathione Transferase / Q000096:biosynthesis*; D006801:Humans; D008113:Liver Neoplasms; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D051379:Mice; D015394:Molecular Structure; D009247:NADH, NADPH Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D013438:Sulfhydryl Compounds / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D001597:Benzylidene Compounds; D002074:Butanones; D002934:Cinnamates; D003374:Coumarins; D003512:Cyclohexanones; D003517:Cyclopentanes; D013438:Sulfhydryl Compounds; C007201:cyclopentanone; D002599:Chalcone; C025383:benzylideneacetone; D038181:FMN Reductase; D009247:NADH, NADPH Oxidoreductases; D005982:Glutathione Transferase; D005978:Glutathione