Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers.
Induction of phase 2 enzymes (e.g., glutathione transferases, NAD(P)H:quinone reductase, glucuronosyltransferases, epoxide hydrolase) is a major strategy for reducing the susceptibility of animal cells to neoplasia and other forms of electrophile toxicity. In a search for new chemoprotective enzyme inducers, a structure-activity analysis was carried out on two types of naturally occurring and synthetic substituted phenylpropenoids: (a) Ar-CH=CH-CO-R, where R is OH, OCH3, CH3, or Ar, including cinnamic, coumaric, ferulic, and sinapic acid derivatives, their ketone analogues, and chalcones; and (b) bis(benzylidene)cycloalkanones, Ar-CH=C(CH2)n(CO)C=CH-Ar, where n = 5, 6, or 7. The potencies of these compounds in inducing NAD(P)H:quinone reductase activity in murine hepatoma cells paralleled their Michael reaction acceptor activity (Talalay, P.; De Long, M. J.; Prochaska, H. J. Proc. Natl. Acad. Sci. U.S.A. 85, 1988, 8261-8265). Unexpectedly, the bis(benzylidene)cycloalkanones also powerfully quenched the lucigenin-derived chemiluminescence evoked by superoxide radicals. Introduction of o-hydroxyl groups on the aromatic rings of these phenylpropenoids dramatically enhanced their potencies not only as inducers for quinone reductase but also as quenchers of superoxide. These potentiating o-hydroxyl groups are hydrogen-bonded, as shown by moderate downfield shift of their proton NMR resonances and their sensitivities to the solvent environment. The finding that the potencies of a series of bis(benzylidene)cycloalkanones in inducing quinone reductase appear to be correlated with their ability to quench superoxide radicals suggests that the regulation of phase 2 enzymes may involve both Michael reaction reactivity and radical quenching mechanisms.
Dinkova-Kostova
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Departments of Pharmacology and Molecular Sciences and of Biological Chemistry, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205, USA.
Abeygunawardana
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Talalay
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D000818:Animals; D016588:Anticarcinogenic Agents / Q000737:chemistry / Q000494:pharmacology*; D002599:Chalcone / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D002934:Cinnamates / Q000737:chemistry / Q000494:pharmacology*; D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004790:Enzyme Induction; D016166:Free Radical Scavengers / Q000737:chemistry / Q000494:pharmacology*; D008114:Liver Neoplasms, Experimental / Q000201:enzymology / Q000473:pathology; D008163:Luminescent Measurements; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D008968:Molecular Conformation; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D016588:Anticarcinogenic Agents; D002934:Cinnamates; D003374:Coumarins; D016166:Free Radical Scavengers; D013481:Superoxides; D002599:Chalcone; D016660:NAD(P)H Dehydrogenase (Quinone)