An optimized pyrimidinol multifunctional radical quencher

Omar Khdour, Pablo M. Arce, Basab Roy, Sidney Hecht

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

A series of aza analogues (4-9) of the experimental neuroprotective drug idebenone (1) have been prepared and evaluated for their ability to attenuate oxidative stress induced by glutathione depletion and to compensate for the decrease in oxidative phosphorylation efficiency in cultured Friedreich's ataxia (FRDA) fibroblasts and lymphocytes and also coenzyme Q10-deficient lymphocytes. Modification of the redox core of the previously reported 3 improved its antioxidant and cytoprotective properties. Compounds 4-9, having the same redox core, exhibited a range of antioxidant activities, reflecting side chain differences. Compounds having side chains extending 14-16 atoms from the pyrimidinol ring (6, 7, and 9) were potent antioxidants. They were superior to idebenone and more active than 3, 4, 5, and 8. Optimized analogue 7 and its acetate (7a) are of interest in defining potential therapeutic agents capable of blocking oxidative stress, maintaining mitochondrial membrane integrity, and augmenting ATP levels. Compounds with such properties may find utility in treating mitochondrial and neurodegenerative diseases such as FRDA and Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)724-729
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume4
Issue number8
DOIs
StatePublished - Aug 8 2013

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Friedreich Ataxia
coenzyme Q10
Oxidative stress
Lymphocytes
Antioxidants
Oxidation-Reduction
Oxidative Stress
Neurodegenerative diseases
Mitochondrial Diseases
Aptitude
Oxidative Phosphorylation
Mitochondrial Membranes
Neuroprotective Agents
Fibroblasts
Neurodegenerative Diseases
Glutathione
Alzheimer Disease
Acetates
Adenosine Triphosphate
Membranes

Keywords

  • adenosine triphosphate
  • cytoprotection
  • electron transport chain
  • lipid peroxidation
  • Mitochondrial dysfunction

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

Cite this

An optimized pyrimidinol multifunctional radical quencher. / Khdour, Omar; Arce, Pablo M.; Roy, Basab; Hecht, Sidney.

In: ACS Medicinal Chemistry Letters, Vol. 4, No. 8, 08.08.2013, p. 724-729.

Research output: Contribution to journalArticle

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