Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: correlation of potencies as phase 2 enzyme inducers and radical scavengers

J Med Chem. 1998 Dec 17;41(26):5287-96. doi: 10.1021/jm980424s.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Anticarcinogenic Agents / chemistry
  • Anticarcinogenic Agents / pharmacology*
  • Chalcone / analogs & derivatives
  • Chalcone / chemistry
  • Chalcone / pharmacology*
  • Cinnamates / chemistry
  • Cinnamates / pharmacology*
  • Coumarins / chemistry
  • Coumarins / pharmacology*
  • Enzyme Induction*
  • Free Radical Scavengers / chemistry
  • Free Radical Scavengers / pharmacology*
  • Liver Neoplasms, Experimental / enzymology
  • Liver Neoplasms, Experimental / pathology
  • Luminescent Measurements
  • Magnetic Resonance Spectroscopy
  • Mice
  • Molecular Conformation
  • NAD(P)H Dehydrogenase (Quinone) / metabolism*
  • Structure-Activity Relationship
  • Superoxides / metabolism
  • Tumor Cells, Cultured


  • Anticarcinogenic Agents
  • Cinnamates
  • Coumarins
  • Free Radical Scavengers
  • Superoxides
  • Chalcone
  • NAD(P)H Dehydrogenase (Quinone)