Reactivity of Peroxynitrite with Melatonin as a Function of pH and CO2 Content

Abstract

Peroxynitrite is known to be a strong oxidant and a nitrating agent of aromatic phenolic or heterocyclic rings, depending on its form in aqueous solutions: the anion ONOO − , its conjugate acid ONOOH, or its CO 2 adduct ONOOCO 2 − . Various reactions have been observed with melatonin (1), a tryptophan derivative, in phosphate-buffered solutions. Melatonin (1) is recognized as a scavenger of several strong oxidants (HO · , H 2 O 2 , ...) accounting for its biological and pharmacological effects. Here we describe two oxidation routes that give rise to indol-2-ones 2 (probably via a 2,3-epoxyindole) and kynuramines 6 (by cleavage of the pyrrole ring), attributable to reactions of ONOOH and ONOO − , respectively, according to the effects of pH and CO 2 content. At pH = 7.6 and in the presence of CO 2 , an important conversion is the cyclization of the lateral amide function, giving 3-substituted pyrroloindoles 4. At neutral pH, therefore, all routes coexist, with a balance between indol-2-ones 2 and pyrroloindoles 4 on the one side and kynuramines 6 on the other, depending on the

Melatonin: A Potential Anti-Oxidant Therapeutic Agent for Mitochondrial Dysfunctions and Related Disorders

“…[71][72][73][74][75] Not only with OH • , c3-OHM is also produced when melatonin scavenges other reactive oxygen species as well like 1 O 2 76 , 77 and ONOO − . 78,79 Melatonin has been shown to act as peroxyl radical (LOO˙) scavenger. 80 Infact it acts as a chain breaking antioxidant during the propagation of lipid peroxidation.…”

Antioxidant and Anti-Inflammatory Role of Melatonin in Alzheimer’s Neurodegeneration

“…39 The resultant nitrosomelatonin may transnitrosate nucleophiles such as thiols and ascorbate. Nitrosation reactions are favored under physiologic, neutral pH in the absence of added bicarbonate.…”

15N-CIDNP investigations during tryptophan,N-acetyl-l-tryptophan, and melatonin nitration with reactive nitrogen species

“…A possible reaction mechanism is given in Scheme 7. Nitration of melatonin (Mel) by peroxynitrite leads to 4-nitromelatonin (4-NO 2 -Mel) as the main product and 6-nitromelatonin (6-NO 2 -Mel) as a side product [16]. In the following, 15 N-CIDNP studies will be described using peroxynitrite-15 N and H 15 NO 4 as nitrating agents.…”

“…In a further part, the nitration of the Trp derivative melatonin (N-[2-(5-methoxy-1H-indol-3yl)-ethyl]-acetamide; Mel) will be described, too. Mel is recognized as a scavenger of strong oxidants [16]. The final pH after mixing was 7.5.…”