Melatonin derivatives, 2-substituted

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. 

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). 

The mechanism of melatonin s interaction with reactive species probably involves donation of an electron to form the melatoninyl cation radical or through a radical addition at the site C3. Other possibilities include hydrogen donation from the nitrogen atom or substitution at position C2, C4, and C7 and nitrosation [169]. The mechanisms by which melatonin protects against LP most likely involve direct or indirect antioxidant and free-radical scavenging activities of this indoleamine [169,171]. 2-Phenyl indole derivatives have redox properties because of the presence of an electron-rich aromatic ring system that allows the indoleamine to easily function as an electron donor. For these derivatives, the possible antioxidant mechanism might be most probably toward carbon-centered radicals described by Antosiewicz et al. [172]. 

As Eilbracht and coworkers [38] showed in numerous examples, the reaction cascade hydroformylation—(Fischer indolization) is a useful protocol for the synthesis of three-substituted indoles, including the essential amino acid tryptophan, the tissue hormone melatonin, and the neutrotransmitter serotonin (Figure 5.25). In addition, pharmacologically active tryptamine or homotryptamine derivatives, such as the marketed serotonin agonists sumatriptan, naratriptan, or zolmitriptan, or compounds that show a platelet aggregation inhibitory and antithrombotic effect (vintoperol) can be synthesized by such a protocol. Also active drug components for the treatment of schizophrenia (sertindole) can probably be produced by this approach [39]. It is estimated that the worldwide demand for such indole derivatives is about 20 000 mt/a [40]. 

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