N‐Nitrosomelatonin: synthesis, chemical properties, potential prodrug

Abstract

: Melatonin is easily nitrosated via various mechanisms at the nitrogen atom of the indole ring to give N‐nitrosomelatonin (NOMela). This Mini‐review provides a comprehensive view of this N‐nitroso compound. With an improved procedure NOMela can now economically synthesized with low laboratory expenditure. The major chemical property of NOMela, i.e. the (formally) transfer of the NO+ function to its target nucleophile, is explained in detail and a variety of detection methods using this reaction are suggested. As the suspected carcinogenical potential of NOMela is clearly overruled it seems attractive to apply this nitroso compound for endogenous generation of S‐nitrosothiols that act as nitric oxide donors in vivo.

Melatonin Metabolism in the Central Nervous System

“…The role of 1-nitrosomelatonin strongly differs from those of the melatonin metabolites formed by interaction with reactive oxygen species, and the nitrosation of this indole should not be misinterpreted in terms of detoxification. 1-Nitrosomelatonin easily re-donates NO [12,16,23] and is likewise capable of transnitrosating other molecules [63,64]. These properties can be either desirable or highly undesirable.…”

“…These properties can be either desirable or highly undesirable. On the one hand, 1-nitrosomelatonin may be used as an amphiphilic NO source, and the idea has been that melatonin regenerated by NO release detoxifies the oxygen radicals formed as a secondary consequence of NO metabolism [12,64]. On the other hand, transnitrosation of especially mitochondrial proteins can cause dysfunction of the respiratory chain and electron leakage [40,48].…”

Encapsulation of N-Nitroso-melatonin with Poly(lactide-co-glycolide)

“…In contrast, melatonin and nitrite were released in a strict 1:1 stoichiometric ratio from uncapsulated NOMela in the absence as well as in the presence of Trolox ( Figure 3B). The data of Figures 3A and 3B also demonstrate that encapsulation significantly increased the half-life time of NOMela from the known value of about 140 min ( Figure 3B, [17]) to >5 h ( Figure 3A).…”

“…The generated product N-nitrosomelatonin was extracted by shaking with dichloromethane (20 mL, 4°C) and the separated, water insoluble organic phase was dried by adding Na 2 SO 4 (750 mg). After removing Na 2 SO 4 this mixture was cooled down to -20°C and taken to evaporation under reduced pressure (18 Torr) to yield about 250 mg N-nitrosotryptophan (Ɛ 346 =7070 M -1 cm -1 [17]). …”

“…Solutions were prepared from 1 ml of released from NOMela had been increased two-to three-fold. Although both hydroxy compounds react with solvated nitrosoindole derivatives with nearly the same rate constant [8,9,17,24], Trolox was a bit more effective than vitamin C in releasing melatonin.…”