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:quino ne reductase, glucuronosyltransferases, epoxide hydrolase) is a major strat egy 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 nat urally occurring and synthetic substituted phenylpropenoids: (a) Ar-CH=CH-C O-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 red uctase 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 chemilumines cence evoked by superoxide radicals. Introduction of o-hydroxyl groups on t he aromatic rings of these phenylpropenoids dramatically enhanced their pot encies not only as inducers for quinone reductase but also as quenchers of superoxide. These potentiating o-hydroxyl groups are hydrogen-bonded, as sh own by moderate downfield shift of their proton NMR resonances and their se nsitivities to the solvent environment. The finding that the potencies of a series of bis(benzylidene)cycloalkanones in inducing quinone reductase app ear to be correlated with their ability to quench superoxide radicals sugge sts that the regulation of phase 2 enzymes may involve both Michael reactio n reactivity and radical quenching mechanisms.