TY - JOUR
T1 - Amphiphilic amide nitrones
T2 - A new class of protective agents acting as modifiers of mitochondrial metabolism
AU - Durand, Grégory
AU - Poeggeler, Burkhard
AU - Ortial, Stéphanie
AU - Polidori, Ange
AU - Villamena, Frederick A.
AU - Böker, Jutta
AU - Hardeland, Rüdiger
AU - Pappolla, Miguel A.
AU - Pucci, Bernard
PY - 2010/7/8
Y1 - 2010/7/8
N2 - 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.
AB - 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.
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U2 - 10.1021/jm100212x
DO - 10.1021/jm100212x
M3 - Article
C2 - 20527971
AN - SCOPUS:77954332672
SN - 0022-2623
VL - 53
SP - 4849
EP - 4861
JO - Journal of medicinal chemistry
JF - Journal of medicinal chemistry
IS - 13
ER -