Amphiphilic amide nitrones: a new class of protective agents acting as modifiers of mitochondrial metabolism.
Our group has demonstrated that the amphiphilic character of alpha-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.
Laboratoire de Chimie BioOrganique et des Systemes Moleculaires Vectoriels, Universite d'Avignon et des Pays de Vaucluse, Faculte des Sciences, 33 Rue Louis Pasteur, 84000 Avignon, France. gregory.durand@univ-avignon.fr
Grégory
G
Durand
Burkhard
B
Poeggeler
Stéphanie
S
Ortial
Ange
A
Polidori
Frederick A
FA
Villamena
Jutta
J
Böker
Rüdiger
R
Hardeland
Miguel A
MA
Pappolla
Bernard
B
Pucci
D000818:Animals; D052160:Benzothiazoles / Q000737:chemistry; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006861:Hydrogen Peroxide / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009589:Nitrogen Oxides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D009904:Optical Rotation; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D021241:Spectrometry, Mass, Electrospray Ionization; D013451:Sulfonic Acids / Q000737:chemistry; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D052160:Benzothiazoles; D016166:Free Radical Scavengers; D009589:Nitrogen Oxides; D013451:Sulfonic Acids; D013501:Surface-Active Agents; C015388:nitrones; C002502:2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid; D006861:Hydrogen Peroxide