Amphiphilic amide nitrones: A new class of protective agents acting as modifiers of mitochondrial metabolism

Grégory Durand, Burkhard Poeggeler, Stéphanie Ortial, Ange Polidori, Frederick A. Villamena, Jutta Böker, Rüdiger Hardeland, Miguel A. Pappolla, Bernard Pucci

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

Our group has demonstrated that the amphiphilic character of α-phenyl-N-tert-butyl nitrone based agents is a key feature in determining their bioactivity and protection against oxidative toxicity. In this work, we report the synthesis of a new class of amphiphilic amide nitrones. Their hydroxyl radical scavenging activity and radical reducing potency were shown using ABTS competition and ABTS•+ reduction assays, respectively. Cyclic voltammetry was used to investigate their redox behavior, and the effects of the substitution of the PBN on the charge density of the nitronyl atoms, the electron affinity, and the ionization potential were computationally rationalized. The protective effects of amphiphilic amide nitrones in cell cultures exposed to oxidotoxins greatly exceeded those exerted by the parent compound PBN. They decreased electron and proton leakage as well as hydrogen peroxide formation in isolated rat brain mitochondria at nanomolar concentration. They also significantly enhanced mitochondrial membrane potential. Finally, dopamine-induced inhibition of complex I activity was antagonized by pretreatment with these agents. These findings indicate that amphiphilic amide nitrones are much more than just radical scavenging antioxidants but may act as a new class of bioenergetic agents directly on mitochondrial electron and proton transport.

Original languageEnglish (US)
Pages (from-to)4849-4861
Number of pages13
JournalJournal of Medicinal Chemistry
Volume53
Issue number13
DOIs
StatePublished - Jul 8 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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    Durand, G., Poeggeler, B., Ortial, S., Polidori, A., Villamena, F. A., Böker, J., Hardeland, R., Pappolla, M. A., & Pucci, B. (2010). Amphiphilic amide nitrones: A new class of protective agents acting as modifiers of mitochondrial metabolism. Journal of Medicinal Chemistry, 53(13), 4849-4861. https://doi.org/10.1021/jm100212x