Melatonin derivatives

Reaction of melatonin with various aryldiazonium chlorides in ethanolic sodium acetate solution afforded arylazo-melatonin derivatives. Reactions of these products with either malonitrile or ethyl cyanoacetate formed the corresponding ary lam inotriazino[4,3-/z indole scaffolds 60-63 <2005BMC1847>. 

The Stille reaction was also reported in the synthesis of melatonin derivatives. Two heating cycles were employed to reach a yield comparable to oil bath heating. The reaction time, two irradiation cycles of 20 minutes, was notably shorter than the 24-hour reaction with standard heating (Scheme 65) [58]. 

Scheme 15.41. Solid-phase synthesis of melatonin derivatives.

Berthault, A., Berteina-Raboin, S., Finaru, A. and Guillaumet, G. (2004) Solid phase s5uithesis of 2-substituted melatonin derivatives via palladium-mediated coupling reactions using microwave irradiation. QSAR Comb. Sci., 23, 850-3. 

Naturally Occurring Compounds. Many derivatives of iadole are found ia plants and animals where they are derived from the amino acid tryptophan. Several of these have important biological function or activity. Serotonin [50-67-9] (12) functions as a neurotransmitter and vasoconstrictor (35). Melatonin [73-31-4] (13) production is controlled daily by the circadian cycle and its physiological level iafluences, and seasonal rhythms ia humans and other species (36). Indole-3-acetic acid [87-51-4] (14) is a plant growth stimulant used ia several horticultural appHcations (37). 

On the other hand, multimodality of biological activities of melatonin is well known. Therefore various derivatives are needed for carrying out its structure-activity relationship study. 1-Hydoxymelatonin (19) would be a suitable seed for developing yet unknown results. 

Figure 22.1 Pathways projecting to and from the suprachiasmatic nucleus (SCN). Inputs from photoreceptors in the retina help to reset the circadian clock in response to changes in the light cycle. Other inputs derive from the lateral geniculate complex and the serotonergic, Raphe nuclei and help to reset the SCN in response to non-photic stimuli. Neurons in the SCN project to the hypothalamus, which has a key role in the regulation of the reproductive cycle, mood and the sleep-waking cycle. These neurons also project to the pineal gland which shows rhythmic changes in the rate of synthesis and release of the hormone, melatonin...

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). 

In another application, the group of Berteina-Raboin demonstrated the solid-supported synthesis of the indole core of melatonin analogues under microwave irradiation (Scheme 7.6) [26]. A benzoic acid derivative was coupled to Rink amide resin by... 

Serotonin is an indolamine neurotransmitter, derived from the amino acid L-tryptophan. Tryptophan is converted to 5-hydroxytryptophan (5-HTP) by tryptophan hydroxylase. 5-HTP is converted to 5-hydroxytryptamine (serotonin, 5-HT) by aromatic amino acid decarboxylase. In the pineal gland, 5-HT may be further converted to /V-acetyl serotonin by 5-HT /V-acetyltransferase and then to melatonin by 5-hyroxyindole-O-methyltransferase. 5-HT is catabolized by monoamine oxidase, and the primary end metabolite is 5-hydroxyindoleacetic acid (5-HIAA). 

Melatonin is A-acetyl-5-methoxytryptamine, a simple derivative of serotonin. It is a natural hormone secreted by the pineal gland in the brain during the hours of darkness. It is involved in controlling the body s day-night... 

Azocino[4,5,6-cd]indoles 61 and 62 have been obtained from the corresponding Af-chloroacetyl derivatives of tryptamine and melatonine with the help of photocyclization. Further, lactam 62 has been reduced to 8-methoxy-3,4,6, 7-tetrahydro-lH,5H-azocino[4,5,6-cd]indole (63) under the action of B2Hg (69JMC(12)636 Scheme 19). 

The best evidences are studies from preclinical animal models [86, 87, 105], or knockout animals lacking appropriate anti-oxidative pathways [106]. For example, Balb/c mice administered a variety of anti-oxidants in their chow were protected from acetaminophen hepatotoxicity [107]. Rats fed with the anti-oxidant melatonin were protected from cholesterol mediated oxidative liver damage [108]. The best clinical evidence that oxidative stress is a key player in a variety of liver injury diseases is the beneficial application of silymarin in these disease indications [109]. Silymarin is a polyphenolic plant fiavonoid (a mixture of flavonoid isomers such as silibinin, isosilibinin, silidianin and silichristin) derived from Silymarin maria-num that has antioxidative, antilipid peroxidative, antifibrotic and anti-inflammatory effects [109, 110]. 

Some prominent 3-substituted derivatives include skatole (3-methylin-dole), which has a faecal odour, and indoIyl-3-acetic acid (sold as a plant rooting powder). Many indoles are biologically important for example, tryptamine is the precursor of two hormones serotonin, a vasoconstrictor, and melatonin, which is involved in the control of circadian rhythm. In addition, the amino acid tryptophan is an essential component of proteins (see Box 7.1). 

Pyrrolopyridine derivatives, 103, can be synthesized from pyridine compounds containing amino, iodo, and/or nitro substituents <1999H(50)1065>. These compounds serve as analogues of melatonin. 

Figure 18.5. Quenching of benzophenone triplet by 0.24-mM melatonin in acetonitrile, monitored at 600 nm following 355-nm laser excitation. Each point is derived from a trace such as that shown in Figure 18.4. The spectrum was recorded at room temperature, under a nitrogen atmosphere. ...

Numerous examples of hydrogen abstraction by rcrt-butoxyl radicals have been reported. The unusual choice of melatonin is not accidental note that the radical has simply been identified as (melatonin) and seems to emphasize that the site of reaction (in fact, rather well established in this case) may not necessarily be derived from the laser experiment. The laser technique observes all sites and forms of reaction regardless of which species is monitored and how well characterized it may be (see below). The trace of Figure 18.7 shows the formation of the melatonin radical following hydrogen transfer to ferf-butoxyl. ... 

It is a sad story to tell, but this subtle shape-shifting is all too often invisible to the researcher. We will learn what melatonin does, by studying its radio-iodinated derivative. We will determine the quality of our synthetic analogs by measuring the displacement they make of iodinated melatonin from the melatonin receptor, lodomelatonin is not melatonin. It is a different compound. It has a different biochemistry and a different pharmacology. It is used in melatonin studies only because it can be seen. Melatonin itself is, by its nature, a dark traveler in a dark forest, and we still do not know how to study it directly. 

Protected and unprotected indole derivatives dissolved in hydrogen fluoride are also fluorinated by 18F-F. The relatively stable melatonin (10), a neurohormone responsible for the biological clock and other brain functions, gave only the 6-[l8F]fluoro derivative 11, but even the more fragile 5-hydroxytryptophan (12) could be fluorinated under these conditions resulting in a mixture of 4- and 6-[l8F]fluorohydroxytryptophan 13.54... 

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