6-Hydroxymelatonin

Many studies of melatonin are accompanied on an idea that many of the effects credited to melatonin may be mediated by some melatonin analogues or metabolites [138], such as by AFMK, a product of the melatonin antioxidant cascade, which is also a potent scavenger of reactive species [139]. Also, the melatonin precursor, N-acetylserolonin, or the melatonin metabolite 6-hydroxymelatonin, which was found a better antioxidant than melatonin itself by authors Zhang and coworkers [140], is considered Melatonin-related indoles that protect and defend against both autooxidation and iron-induced peroxidation of lipids [141]. 

Maharaj, D.S., Walker, R.B., Glass, B.D., Daya, S. (2003). 6-Hydroxymelatonin protects against cyanide induced oxidative stress in rat brain homogenates. J. Chem. Neuroanat. 26 103-7. 

As a neurohormone, melatonin is a poor drug because of its poor absorption, low oral bioavailability (<10%), rapid first-pass metabolism by CYP1A2 to 6-hydroxymelatonin (its primary metabolite), and ubiquitous effects. In their... 

M is synthesized from serotonin by acetylation to A-acetyl rotonin, followed by methylation (catalysed by acetylserotonin methyltransferase, EC 2.1.1.4) to M.In the pineal gland M. biosynthesisis is controlled by epinephrine, which stimulates adenylate t clase (EC 4.6.1.1), which in turn stimulates protein kinase. The first three steps of M. synthesis (L-tryptophan S-hydroxytryptophan -> serotonin - A-acetyl-5-hydroxytryptamine) are promoted in this way, but the methyltransferase is not affected. However, the rate-limiting step is catalysed by serotonin A-acetyltransferase. M. is inactivated and excreted as 6-hydroxymelatonin, or as 5-methoxyindole-acetic acid. 

Specific Quantitation of Urinary 6-Hydroxymelatonin Sulfate by Gas Chromatography-Mass Spectrometry Biomed. Mass Spectrom. 7(2) 84-87... 

Measurement of 6-Hydroxymelatonin in Human Urine and Its Diurnal Variations... 

The sulfate esters of 6-hydroxymelatonin and V-acetylseratonin have been prepared by reaction of the parent compounds with chlorosulfonic acid in DMF sulfation by this procedure is simple and rapid. The natural metabolite of melatonin, melatonin-6-sulfate, has been demonstrated to be identical to the synthetic product. ... 

When 1-hydroxymelatonin (19) is treated with acid, removal of its 1-hydroxy group leaves an indolyl cation (a hybrid of resonance structures 254,168, and so on) as shown in Scheme 37. If there is a subsequent intramolecular nucleophilic attack by the Ab-nitrogen atom on the side chain or if an intermolecular attack by suitable nucleophiles occurs on this intermediate cation, the birth of a new type of product can be expected. 

Melatonin can be metabolized non-enzymatically in all cells, and extra-cellularly by free radicals and a few other oxidants. It is converted into cyclic 3-hydroxymelatonin when it directly scavenges two hydroxyl radicals (Tan et al. 1998). In the brain, a substantial fraction of melatonin is metabolized to kynuramine derivatives (Hirata et al. 1974). AFMK is produced by numerous non-enzymatic and enzymatic mechanisms (Hardeland et al. 2006) its formation by myeloperoxidase appears to be important in quantitative terms (Ferry et al. 2005). 

Tan, D. X., Manchester, L. C., Reiter, R. J. et al. (1998). A novel melatonin metabolite, cyclic 3-hydroxymelatonin a biomarker of in vivo hydroxyl radical generation. Biochem. Biophys. Res. Comm. 253, 614-20. 

The p/Ta values of the 1-hydroxy moiety of (S)-(- -)-AIb-acetyl-l-hydroxytrypto-phan methyl ester (32), methyl l-hydroxyindole-3-butylate (33), Mb-methoxy-carbonyl-1-hydroxytryptamine (34), l-hydroxymelatonin (19), l-hydroxy-6-nitroindole (35), and l-hydroxy-5-nitroindole (36) are determined to be 9.8, 8.4, 8.2,8.1, 6.9, and 6.8, respectively (Fig. 2) (2000H1881). Thus, 1-hydroxyindoles are weak acids, stronger than phenol and weaker than succinimide. Therefore,... 

With an attempt to develop a synthetic method for pyrrolo[2,3-fc]mdoles having a C - C bond at the 3a-position like 160, TsCl (or MsCl) is added to a mixture of 1-hydroxymelatonin (161), l-(4-morpholinyl)cyclohexene (162), and EtsNinCHCls. An unusual reaction has occurred, though it s based on the nature of l-hydroxyindole skeletons products are Nb-acetyl-3-hydroxy-5-methoxy-2-(4-morpholinyl)-3H-indole-3-ethanamine (163a, 37%), 2-[3-(2-acetylaminoethyl)-5-methoxy-3H-indol-3-yl] cyclohexanone (164, 4%), and melatonin (64, 8%) (Scheme 21) [40]. The same reaction of 1-hydroxy-Mb-methoxycarbonylindole-3-ethanamine (52) provides 3-hydroxy-M)-methoxy-carbonyl-2-(4-morpholinyl)-3ff-indole-3-ethanamine (163b, 44%) and Mb-methoxycarbonyl-6-tosyloxyindole-3-ethanamine (165, 11%). 

Using mass spectrometry, proton nuclear magnetic resonance ( H NMR), COSY H NMR analysis, and calculation on the relative thermodynamic stability, Tan et al. (1998) identified a novel melatonin metabolite as cyclic 3-hydroxymelatonin. This is the product of reaction of melatonin with HO generated in two different cell-free in vitro systems. Cyclic 3-hydroxymelatonin also existed in urine of both human and rat. When rats were challenged with ionising radiation (800 cGy = LD50 for a one month period), as expected, urinary cyclic 3-hydroxymelatonin was doubled over that of the controls (P = 0.002). 

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