Enolate-Forming Compounds as a Novel Approach to Cytoprotection

Richard M. LoPachin, Brian C. Geohagen, Larsulrik R. Nordstroem, Terrence Gavin

Research output: Contribution to journalReview article

2 Citations (Scopus)

Abstract

Evidence from laboratory studies and clinical trials suggests that plant-derived polyphenolic compounds such as curcumin, resveratrol, or phloretin might be useful in the treatment of certain diseases (e.g., Alzheimer's disease) and acute tissue injury states (e.g., spinal cord trauma). However, despite this potential, the corresponding chemical instability, toxic potential, and low bioavailability of these compounds could limit their ultimate clinical relevance. We have shown that pharmacophores of curcumin (e.g., 2-acetylcyclopentanone) and phloretin (e.g., 2′,4′,6′-trihydroxyacetophenone; THA) can provide cytoprotection in cell culture and animal models of oxidative stress injury. These pharmacophores are 1,3-dicarbonyl and polyphenol derivatives, the enol groups of which can ionize in biological solutions to form an enolate. This carbanionic moiety can chelate metal ions and, as a nucleophile, can scavenge toxic electrophiles (e.g., acrolein, 4-hydroxy-2-nonenal, and N-acetyl-p-benzoquinone imine) involved in many pathogenic conditions. Aromatic derivatives such as THA can also trap free oxygen and nitrogen radicals and thereby provide another layer of cytoprotection. The multifunctional character of these enolate-forming compounds suggests an ability to block pathogenic processes (e.g., oxidative stress) at several steps. The purpose of this review is to discuss research supporting our theory that enolate formation is a significant cytoprotective property that represents a platform for development of pharmacotherapeutic approaches to a variety of toxic and pathogenic conditions. Our discussion will focus on mechanism and structure-activity studies that define enolate chemistry and their corresponding relationships to cytoprotection.

Original languageEnglish (US)
Pages (from-to)2096-2107
Number of pages12
JournalChemical Research in Toxicology
Volume29
Issue number12
DOIs
StatePublished - Dec 19 2016

Fingerprint

Cytoprotection
Poisons
Phloretin
Tacrine
Curcumin
Oxidative stress
Oxidative Stress
Polyphenolic compounds
Derivatives
Acrolein
Nucleophiles
Aptitude
Imines
Wounds and Injuries
Phytochemicals
Polyphenols
Spinal Cord Injuries
Cell culture
Biological Availability
Metal ions

ASJC Scopus subject areas

  • Toxicology

Cite this

Enolate-Forming Compounds as a Novel Approach to Cytoprotection. / LoPachin, Richard M.; Geohagen, Brian C.; Nordstroem, Larsulrik R.; Gavin, Terrence.

In: Chemical Research in Toxicology, Vol. 29, No. 12, 19.12.2016, p. 2096-2107.

Research output: Contribution to journalReview article

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