Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors

Correlation of potencies as phase 2 enzyme inducers and radical scavengers

Albena T. Dinkova-Kostova, Chitrananda Abeygunawardana, Paul Talalay (Lead / Corresponding author)

Research output: Contribution to journalArticle

170 Citations (Scopus)

Abstract

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 down field 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.

Original languageEnglish
Pages (from-to)5287-5296
Number of pages10
JournalJournal of Medicinal Chemistry
Volume41
Issue number26
DOIs
Publication statusPublished - 17 Dec 1998

Fingerprint

NAD(P)H Dehydrogenase (Quinone)
Superoxides
ferulic acid
Enzymes
Carbon Monoxide
Hydroxyl Radical
NAD
Chalcones
Epoxide Hydrolases
Coumaric Acids
Glucuronosyltransferase
Luminescence
Glutathione Transferase
Ketones
Protons
Hydrogen
Hepatocellular Carcinoma
Neoplasms

Cite this

@article{72db3c6bc40643c98bc27f6e1a7e5d83,
title = "Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors: Correlation of potencies as phase 2 enzyme inducers and radical scavengers",
abstract = "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 down field 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.",
author = "Dinkova-Kostova, {Albena T.} and Chitrananda Abeygunawardana and Paul Talalay",
year = "1998",
month = "12",
day = "17",
doi = "10.1021/jm980424s",
language = "English",
volume = "41",
pages = "5287--5296",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "26",

}

Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors : Correlation of potencies as phase 2 enzyme inducers and radical scavengers. / Dinkova-Kostova, Albena T.; Abeygunawardana, Chitrananda; Talalay, Paul (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 41, No. 26, 17.12.1998, p. 5287-5296.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Chemoprotective properties of phenylpropenoids, bis(benzylidene)cycloalkanones, and related Michael reaction acceptors

T2 - Correlation of potencies as phase 2 enzyme inducers and radical scavengers

AU - Dinkova-Kostova, Albena T.

AU - Abeygunawardana, Chitrananda

AU - Talalay, Paul

PY - 1998/12/17

Y1 - 1998/12/17

N2 - 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 down field 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.

AB - 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 down field 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.

UR - http://www.scopus.com/inward/record.url?scp=0032542331&partnerID=8YFLogxK

U2 - 10.1021/jm980424s

DO - 10.1021/jm980424s

M3 - Article

VL - 41

SP - 5287

EP - 5296

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 26

ER -