1-Hydroxyindoles, 1-hydroxytryptophans

In this review, our recent developments in the chemistry of 1-hydroxyindoles, 1-hydroxytryptophans, and 1-hydroxytryptamines, attained between the beginning of 1999 and the end of May 2001, are summarized together with results obtained... 

Somei, M., Recent Advances in the Chemistry of 1-Hydroxyindoles, 1-Hydroxytryptophans, and 1-Hydroxytryptamines, 82, 101. 

Homolytic substitution of heteroaromatic compounds, 16, 123 Hydantoins, chemistry of, 38, 177 Hydrogen cyanide derivatives, synthesis of heterocycles from, 41, 1 Hydrogen exchange base-catalyzed, 16, 1 one-step (labeling) methods, 15, 137 Hydrogenated porphyrin derivatives hydroporphyrins, 43, 73 Hydroxamic acids, cyclic, 10, 199 1 -Hydroxyindoles, 1 -hydroxytryptophans, and 1-hydroxytryptamines,... 

As a result, we could open the door to a new frontier in indole chemistry. Various 1-hydroxyindoles (4a), l-hydroxytryptophans(la), 1-hydroxytryptamines (lb), and their derivatives have been given birth for the first time. As predicted, 1-hydroxytryptophan and 1-hydroxytryptamine derivatives are found to undergo previously unknown nucleophilic substitution reactions. In addition, we have been uncovering many interesting reactivities characteristic of 1-hydroxyindole structures. From the synthetic point of view, useful building blocks for indole alkaloids, hither to inaccessible by the well-known electrophilic reactions in indole chemistry, have now become readily available. Many biologically interesting compounds have been prepared as well. 

Hydroxyindoles carrying a side chain containing a free NH2, OH, or COOH functional group are unstable. Therefore, 1-hydroxytryptophan, -tryptamine, and -indole-3-acetic acid have not been prepared yet. 

In contrast, substrates having other struetural types of side ehain at the 3 position dimerize under aeidie eonditions, and never produee the 5-substituted produets. These faets seem to support the 1-Hydroxyindole Hypotheses, whieh elaim the formation of serotonin from 1-hydroxytryptophan and/or -tryptamine in the aeidie eompartment within eukaryotie eells. 

Figure 9 Chromatogram of 5-hydroxyindoles derivatized with 6-AMP. Peaks (2.5 pmol each on column) 1 = 5-hydroxytryptophan 2 = serotonin 3 = 5-hydroxyindole-3-acetic acid. (From Ref. 50.)...

It therefore appears that the main action of reserpine is to produce a biochemical change so that the cells no longer retain a high concentration of serotonin. In other words, the binding of serotonin is prevented. Thus, after the administration of 5-hydroxytryptophan (a precursor of serotonin) to rabbits pretreated with reserpine, serotonin is rapidly formed but remains in a free form. Presumably, free serotonin, before it is metabolized to 5-hydroxyindole acetic acid by amine... 

Both these 5-hydroxyindoles are natural compounds, playing an important role in the brain. 5-hydroxytryptophan (5-HTP) 315 is the metabolic precursor for the neurotransmitter serotonin melatonin 316 is a neurohormone involved in the regulation of chronobiological rhythms such as sleep and fertility306. They have been labelled with F-18, for in vivo metabolic imaging with PET, in reaction of dilute [18F]fluorine gas with melatonin or with 5-hydroxytryptophan in hydrogen fluoride307 at — 70 °C (equation 134). 

Fig. 5 Tryptophrin is converted to 5-hydroxytryptophan by tryptophan hydroxylase (1). The production of serotonin in the next step is catalysed by 5-HTP decaiboxylase (a PLP-dependent enzyme). Serotonin is then acetylated to N-acetyl-serotonin by N-acetyltransferase (2). Melatonin is then produced via the action of hydroxyindole-O-methyltransferase (3)...

The sedative effect of palmatine on locomotor activity and concentration of monoamine in rats was studied via behavioral and biochemical methods. Palmatine was shown to enhance the hypomotility induced by a-methyl-p-tyrosine, reserpine, and 5-hydroxytryptophan, but reduced the hypermotility produced by L-dopa plus benserazide and p-chlorophenylalanine. In addition, the alkaloid significantly decreased the concentration of dopamine and homovanillic acid in the cortex and the concentration of serotonin in the brain stem, but increased the concentration of 5-HT in the cortex and 5-hydroxyindole acetic acid in the brain stem. These results suggest that the sedative action associated with palmatine may be related to the decrease in catecholamine concentration in the cortex and serotonin in the brain stem, and the increase in the concentration of 5-HT in the cortex [309],... 

The hydroxylation of tryptophan produces 5-hydroxytryptophan, which can then be decarboxylated, catalyzed by tryptophan decarboxylase, a PALP-requiring enzyme, to 5-hydroxy tryptamine, also known as serotonin. Serotonin is an important compound in normal brain function and tranquility. Therefore, any disturbance of tryptophan metabolism via this pathway can lead to mental disturbances. Serotonin can be destroyed by the enzyme monoamine oxidase (a flavo protein), which catalyzes the formation of ammonia and 5-hydroxyindole acetaldehyde in an irreversible reaction. The aldehyde is rapidly oxidized enzymatically, utilizing NAD+ to form 5-hydroxy indoleacetate, which is then usually excreted. The formation and turnover of serotonin can be estimated by 5-hydroxy indoleacetate output in the urine. 

Serotonin, or 5-HT, is biosynthesized (3) from its dietary precursor L-tryptophan (Fig. 14.1). Serotonergic neurons contain tryptophan hydroxylase (L-tryptophan-5-monooxygenase) that converts tryptophan to 5-hydroxytryptophan (5-HTP) in what is the rate-limiting step in 5-HT biosynthesis and aromatic L-amino acid decarboxylase (previously called 5-HTP decarboxylase) that decarboxylates 5-HTP to 5-HT. This latter enzyme also is responsible for the conversion of L-DOPA to dopamine (see Chapter 12). The major route of metabolism for 5-HT is oxidative deamination by monoamine oxidase (MAO-A) to the unstable 5-hydroxyindole-3-acetaldehyde, which is either reduced to 5-hydroxytryptophol ( 15%) or oxidized to 5-hydroxyindole-3-acetic acid ( -85%). In the pineal gland, 5-HT is acetylated by 5-HT N-acetyltransferase to N-acetylserotonin, which undergoes O-methylation by 5-hydroxyindole-O-methyltransferase to melatonin. 

Somei et al. have also shown that nucleophilic additions occur on the indole nucleus of 1-hydroxyindole and 1-hydroxytryptophan residues in the presence of 85% formic acid [3]. For example, indole displaces the hydroxyl group from (DL)-1-hydroxytryptophan methyl ester (106) to provide the l-(indol-3-yl)indole 107 in 51% yield. When other nucleophiles such as phenol, naphthol, and pyrrole are used, a more complicated mixture of products is isolated. 

Somei M (2006) A Frontier in indole chemistry 1-hydroxyindoles, 1-hydroxytryptamines, and 1-hydroxytryptophans. In Topics in heterocyclic chemistry. Springer, Berlin/Heidelberg, pp 77-111... 

Various acids promote the substitution reaction of 1-hydroxyindoles, 1-hy-droxytryptamines, and 1-hydroxytryptophans with nucleophiles. We have demonstrated that pKa of the organic acids has a remarkable effect on the reaction employing 1-hydroxy-Nb-methoxycarbonyltryptamine (52) as a substrate [33]. As can be seen from Table 5, neither propionic nor acetic acids have sufficient acidity for inducing the substitution reaction. They yield a slight quantity of dehydroxylated tryptamine (55) (entries 1-2). As the acidity increases, the yield of 5-hydroxytryptamine (104a), a product of nucleo-... 

In our 1-hydroxyindole hypothesis, we had predicted that 5-hydroxy-tryptamines (serotonins) and 5-hydroxytryptophans were supplied from the 1-hydroxytryptophan residues in the tryptophans-containing peptides by the mediation of acids that are hnked with the TCA (Kreb s) cycle [2,5-7]. 

---