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 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.

Inhibition of ROS-induced apoptosis in endothelial cells by nitrone spin traps via induction of phase II enzymes and suppression of mitochondria-dependent pro-apoptotic signaling

“…DMPO has been widely employed as spin trapping agents with more superior properties than that of PBN-based nitrones in terms of reactivity to O 2 •− and HO 2 • [76]. Therefore, attempts had been made to conjugate cyclic nitrones to several target specific groups in order to facilitate their delivery to specific subcellular compartments [34, 78–80] since the poor target specificity of some of the natural antioxidants such as vitamin E, vitamin C, or lipoic acid are limiting their applications against ROS-induced CVDs [19, 81, 82]. …”

Reactivities of Substituted α-Phenyl-N-tert-butyl Nitrones

“…First, 2-methyl-2-nitro-1-propanol was activated using 1,1′-carbonyldiimidazole (CDI) in the presence of 4-dimethylaminopyridine (DMAP) in THF, and then methylamine was added to the reaction mixture to give compound 3 after purification in 98% yield. In parallel, 2-methyl-2-nitropropanamine ( 4 ) was obtained from 2-methyl-2-nitro-1-propanol in three steps 9 and was then acetylated to give the nitro compound 5 in 94% yield. The one-pot reduction/condensation of compounds 3 and 5 to benzaldehyde after purification by flash chromatography and two successive crystallization from EtOAc/ n -hexane led to nitrones 6 (also called PBN-CH 2 OCONHMe) and 7 (also called PBN-CH 2 NHAc) in 70% and 68% yields, respectively.…”

“…7−9 Selective targeting is usually achieved by conjugating the nitronyl group to specific target ligands, and therefore, the choice of linker groups for optimal spin trapping properties is highly desirable. In addition to the types of ligands that are tethered to nitrones, it has been demonstrated that the nature of the linker group also affects its bioactivity.…”

NO and HNO donors, nitrones, and nitroxides: Past, present, and future

“…New amphiphilic noncyclic nitrones, bearing a polar lactobionic acid moiety and an alkyl lipophilic chain, have been developed by Durand et al Compound 26 (Table ) effectively decreased electron and proton leak and hydrogen peroxide formation in isolated rat brain mitochondria, without affecting the mitochondrial membrane potential. Due to its ability to accumulate in mitochondria, it can act as a radical scavenger in situ and prevent ROS/RNS‐induced mitochondrial dysfunction.…”