Phenolic Michael reaction acceptors: Combined direct and indirect antioxidant defenses against electrophiles and oxidants

A. T. Dinkova-Kostova, J. Cheah, A. Samouilov, J. L. Zweier, R. E. Bozak, R. J. Hicks, P. Talalay

Research output: Contribution to journalArticle

38 Citations (Scopus)

Abstract

The implications of oxidative stress in the pathogenesis of many chronic human diseases has led to the widely accepted view that low molecular weight antioxidants could be beneficial and postpone or even prevent these diseases. Small molecules of either plant or synthetic origins, which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron-withdrawing groups) protect against the toxicity of oxidants and electrophiles indirectly, i.e., by inducing phase 2 cytoprotective enzymes. Some of these molecules, e.g., flavonoid and curcuminoid analogues that have phenolic hydroxyl groups in addition to Michael acceptor centers, are also potent direct antioxidants, and may therefore be appropriately designated: bifunctional antioxidants. By use of spectroscopic methods we identified phenolic chalcone and bis(benzylidene)acetone analogues containing one or two Michael acceptor groups, respectively, as very efficient scavengers of two different types of radicals: (a) the nitrogen-centered 2,2′-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS+) radical cation, and (b) the oxygen-centered galvinoxyl (phenoxyl) radical. The most potent scavengers are those also bearing hydroxyl substituents on the aromatic ring(s) at the ortho-position(s). The initial reaction velocities are very rapid and concentration-dependent. In the human keratinocyte cell line HaCaT, the same compounds coordinately increase the intracellular levels of glutathione, glutathione reductase, and thioredoxin reductase. Thus, such bifunctional antioxidants could exert synergistic protective effects against oxidants and electrophiles which represent the principal biological hazards by: (i) scavenging hazardous oxidants directly and immediately; and (ii) inducing the phase 2 response to prevent and resolve the consequences of hazardous processes that are already in progress, i.e., acting indirectly, but with much more diverse and long-lasting effects.

Original languageEnglish
Pages (from-to)261-268
Number of pages8
JournalMedicinal Chemistry
Volume3
Issue number3
DOIs
Publication statusPublished - 1 May 2007

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Oxidants
Antioxidants
Hydroxyl Radical
Thioredoxin-Disulfide Reductase
Chalcone
Alkynes
Sulfonic Acids
Glutathione Reductase
Alkenes
Acetone
Keratinocytes
Flavonoids
Glutathione
Cations
Oxidative Stress
Chronic Disease
Nitrogen
Molecular Weight
Electrons
Oxygen

Keywords

  • ABTS radical
  • Direct antioxidant
  • Galvinoxyl radical
  • Glutathione
  • Indirect antioxidant
  • Phase 2 inducer
  • Phenolic Michael acceptor
  • Phenoxyl radical

Cite this

Dinkova-Kostova, A. T. ; Cheah, J. ; Samouilov, A. ; Zweier, J. L. ; Bozak, R. E. ; Hicks, R. J. ; Talalay, P. / Phenolic Michael reaction acceptors : Combined direct and indirect antioxidant defenses against electrophiles and oxidants. In: Medicinal Chemistry. 2007 ; Vol. 3, No. 3. pp. 261-268.
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Phenolic Michael reaction acceptors : Combined direct and indirect antioxidant defenses against electrophiles and oxidants. / Dinkova-Kostova, A. T.; Cheah, J.; Samouilov, A.; Zweier, J. L.; Bozak, R. E.; Hicks, R. J.; Talalay, P.

In: Medicinal Chemistry, Vol. 3, No. 3, 01.05.2007, p. 261-268.

Research output: Contribution to journalArticle

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T2 - Combined direct and indirect antioxidant defenses against electrophiles and oxidants

AU - Dinkova-Kostova, A. T.

AU - Cheah, J.

AU - Samouilov, A.

AU - Zweier, J. L.

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AU - Hicks, R. J.

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AB - The implications of oxidative stress in the pathogenesis of many chronic human diseases has led to the widely accepted view that low molecular weight antioxidants could be beneficial and postpone or even prevent these diseases. Small molecules of either plant or synthetic origins, which contain Michael acceptor functionalities (olefins or acetylenes conjugated to electron-withdrawing groups) protect against the toxicity of oxidants and electrophiles indirectly, i.e., by inducing phase 2 cytoprotective enzymes. Some of these molecules, e.g., flavonoid and curcuminoid analogues that have phenolic hydroxyl groups in addition to Michael acceptor centers, are also potent direct antioxidants, and may therefore be appropriately designated: bifunctional antioxidants. By use of spectroscopic methods we identified phenolic chalcone and bis(benzylidene)acetone analogues containing one or two Michael acceptor groups, respectively, as very efficient scavengers of two different types of radicals: (a) the nitrogen-centered 2,2′-azinobis-(3-ethyl-benzothiazoline-6-sulfonic acid) (ABTS+) radical cation, and (b) the oxygen-centered galvinoxyl (phenoxyl) radical. The most potent scavengers are those also bearing hydroxyl substituents on the aromatic ring(s) at the ortho-position(s). The initial reaction velocities are very rapid and concentration-dependent. In the human keratinocyte cell line HaCaT, the same compounds coordinately increase the intracellular levels of glutathione, glutathione reductase, and thioredoxin reductase. Thus, such bifunctional antioxidants could exert synergistic protective effects against oxidants and electrophiles which represent the principal biological hazards by: (i) scavenging hazardous oxidants directly and immediately; and (ii) inducing the phase 2 response to prevent and resolve the consequences of hazardous processes that are already in progress, i.e., acting indirectly, but with much more diverse and long-lasting effects.

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