Studies of structure-activity relationship of nitroxide free radicals and their precursors as modifiers against oxidative damage

Murali C. Krishna, William DeGraff, Olga H. Hankovszky, Cecília P. Sár, T. Kalai, J. Jekó́, Angelo Russo, James B. Mitchell, K. Hideg

Research output: Contribution to journalArticle

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Abstract

The protective effects of stable nitroxides, as well as their hydroxylamine and amine precursors, have been tested in Chinese hamster V79 cells subjected to H2O2 exposure at fixed concentration or exposure to ionizing radiation. Cytotoxicity was evaluated by monitoring the viability of the cells assessed by the clonogenic assay. The compounds tested at fixed concentration varied in terms of ring size, oxidation state, and ring substituents. Electrochemical studies were carried out to measure the redox midpoint potentials. The studies show-that in the case of protection against H2O2 exposure, the protection was determined-by the ring size, oxidation state, and redox midpoint potentials. In general the protection factors followed the order nitroxides > hydroxylamines > amines. Both the six- membered ring nitroxides and substituted five-membered ring nitroxides were efficient protectors. For six-membered ring nitroxides, the compounds exhibiting the lowest midpoint potentials exhibited maximal protection. In the case of X-radiation, nitroxides were the most protective though some hydroxylamines were also efficient. The amines were in some cases found to sensitize the toxicity of aerobic radiation exposure. The protection observed by the nitroxides was not dependent on the ring size. However, the ring substituents had significant influence on the protection. Compounds containing a basic side chain were found to provide enhanced protection. The results in this study suggest that these compounds are novel antioxidants which can provide cytoprotection in mammalian cells against diverse types of oxidative insult and identify structural determinants optimal for protection against individual types of damage.

Original languageEnglish
Pages (from-to)3477-3492
Number of pages16
JournalJournal of Medicinal Chemistry
Volume41
Issue number18
DOIs
Publication statusPublished - Aug 27 1998

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Structure-Activity Relationship
Hydroxylamines
Free Radicals
Amines
Oxidation-Reduction
Cells
Colony-Forming Units Assay
Radiation
Oxidation
Hydroxylamine
Cytoprotection
Ionizing radiation
Cytotoxicity
Cricetulus
Ionizing Radiation
Toxicity
Assays
Antioxidants
X-Rays
Monitoring

ASJC Scopus subject areas

  • Organic Chemistry

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Studies of structure-activity relationship of nitroxide free radicals and their precursors as modifiers against oxidative damage. / Krishna, Murali C.; DeGraff, William; Hankovszky, Olga H.; Sár, Cecília P.; Kalai, T.; Jekó́, J.; Russo, Angelo; Mitchell, James B.; Hideg, K.

In: Journal of Medicinal Chemistry, Vol. 41, No. 18, 27.08.1998, p. 3477-3492.

Research output: Contribution to journalArticle

Krishna, Murali C. ; DeGraff, William ; Hankovszky, Olga H. ; Sár, Cecília P. ; Kalai, T. ; Jekó́, J. ; Russo, Angelo ; Mitchell, James B. ; Hideg, K. / Studies of structure-activity relationship of nitroxide free radicals and their precursors as modifiers against oxidative damage. In: Journal of Medicinal Chemistry. 1998 ; Vol. 41, No. 18. pp. 3477-3492.
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