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 Pappolla, Bernard Pucci

Research output: Contribution to journalArticle

19 Citations (Scopus)

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

Fingerprint

Protective Agents
Amides
Protons
Electrons
Mitochondrial Membrane Potential
Electron Transport
Hydroxyl Radical
Hydrogen Peroxide
Energy Metabolism
Oxidation-Reduction
Dopamine
Mitochondria
Cell Culture Techniques
Antioxidants
nitrones
Brain
2,2'-azino-di-(3-ethylbenzothiazoline)-6-sulfonic acid

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Durand, G., Poeggeler, B., Ortial, S., Polidori, A., Villamena, F. A., Böker, J., ... 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

Amphiphilic amide nitrones : A new class of protective agents acting as modifiers of mitochondrial metabolism. / Durand, Grégory; Poeggeler, Burkhard; Ortial, Stéphanie; Polidori, Ange; Villamena, Frederick A.; Böker, Jutta; Hardeland, Rüdiger; Pappolla, Miguel; Pucci, Bernard.

In: Journal of Medicinal Chemistry, Vol. 53, No. 13, 08.07.2010, p. 4849-4861.

Research output: Contribution to journalArticle

Durand, G, Poeggeler, B, Ortial, S, Polidori, A, Villamena, FA, Böker, J, Hardeland, R, Pappolla, M & Pucci, B 2010, 'Amphiphilic amide nitrones: A new class of protective agents acting as modifiers of mitochondrial metabolism', Journal of Medicinal Chemistry, vol. 53, no. 13, pp. 4849-4861. https://doi.org/10.1021/jm100212x
Durand, Grégory ; Poeggeler, Burkhard ; Ortial, Stéphanie ; Polidori, Ange ; Villamena, Frederick A. ; Böker, Jutta ; Hardeland, Rüdiger ; Pappolla, Miguel ; Pucci, Bernard. / Amphiphilic amide nitrones : A new class of protective agents acting as modifiers of mitochondrial metabolism. In: Journal of Medicinal Chemistry. 2010 ; Vol. 53, No. 13. pp. 4849-4861.
@article{0dace7411a484486bb0427046bb11a2e,
title = "Amphiphilic amide nitrones: A new class of protective agents acting as modifiers of mitochondrial metabolism",
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.",
author = "Gr{\'e}gory Durand and Burkhard Poeggeler and St{\'e}phanie Ortial and Ange Polidori and Villamena, {Frederick A.} and Jutta B{\"o}ker and R{\"u}diger Hardeland and Miguel Pappolla and Bernard Pucci",
year = "2010",
month = "7",
day = "8",
doi = "10.1021/jm100212x",
language = "English (US)",
volume = "53",
pages = "4849--4861",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "13",

}

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

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.

UR - http://www.scopus.com/inward/record.url?scp=77954332672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77954332672&partnerID=8YFLogxK

U2 - 10.1021/jm100212x

DO - 10.1021/jm100212x

M3 - Article

C2 - 20527971

AN - SCOPUS:77954332672

VL - 53

SP - 4849

EP - 4861

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 13

ER -