Indole derivatives importance

Colourless solid m.p. 132-134 C. An important intermediate for preparing indole derivatives, produced by treating indole under Mannich reaction conditions with methanal and dimethylamine. 

One of the virtues of the Fischer indole synthesis is that it can frequently be used to prepare indoles having functionalized substituents. This versatility extends beyond the range of very stable substituents such as alkoxy and halogens and includes esters, amides and hydroxy substituents. Table 7.3 gives some examples. These include cases of introduction of 3-acetic acid, 3-acetamide, 3-(2-aminoethyl)- and 3-(2-hydroxyethyl)- side-chains, all of which are of special importance in the preparation of biologically active indole derivatives. Entry 11 is an efficient synthesis of the non-steroidal anti-inflammatory drug indomethacin. A noteworthy feature of the reaction is the... 

Synthetic Derivatives of Indoles as Pharmaceuticals. Thousands of indole derivatives have been prepared and evaluated as potential pharmaceuticals (32). Of those which have been put into use perhaps the most important are the nonsteroidal antiinflammatory agent indomethacin [53-86-1] (10) (33) and the p-adrenergic blocker pindolol [13823-86-9] (11) (34). 

From a commercial viewpoint the most important compounds of this class are the 3,3-(bisindol-3-yl)phthalides. The first synthesis47 involved Route B as described in Scheme 7, in which a second indole derivative condenses with the indolylbenzoylbenzoic acid in acetic anhydride. However, for the preparation of symmetrical derivatives it has been shown61 that a one-pot process, avoiding isolation of the intermediate and use of aluminum chloride, is more convenient. 

The central importance of the indole derivatives serotonin and the amino acid tryptophan in living organisms has inspired chemists to design and synthesize thousands of indole-containing... 

Some rather important indole derivatives influence our everyday lives. One of the most common ones is tryptophan, an indole-containing amino acid found in proteins (see Section 13.1). Only three of the protein amino acids are aromatic, the other two, phenylalanine and tyrosine being simple benzene systems (see Section 13.1). None of these aromatic amino acids is synthesized by animals and they must be obtained in the diet. Despite this, tryptophan is surprisingly central to animal metabolism. It is modified in the body by decarboxylation (see Box 15.3) and then hydroxylation to 5-hydroxytryptamine (5-HT, serotonin), which acts as a neurotransmitter in the central nervous system. 

Another important example of oxidative cyclization leading to bridgehead heterocyclic compound is the conversion of indole derivative 211... 

Important indole derivatives (see Scheme 2) include (i) indigo, a vat dye known and widely used since antiquity, and originally obtained from indican, a (3-glucoside of indoxyl which occurs in some plants. Indigo is now prepared synthetically. Tyrian purple, a natural dye used since classical times, is 6,6 -dibromoindigo (ii) the numerous indole alkaloids, with complex derivatives such as yohimbine and strychnine (iii) tryptophan, an essential amino acid found in most proteins. Its metabolites include skatole and tryptamine and (iv) 3-indoleacetic acid, which is important as a plant growth hormone. 

Terpenoid Indole Alkaloids.—Important recent work has defined strictosidine (97) as a key intermediate in the biosynthesis of terpenoid indole alkaloids with both 3a- and 3/3-configurations. Some of this work, published earlier in preliminary form (cf. Vol. 9, p. 18), is now available in a full paper.26 In addition to those alkaloids examined earlier, strychnine, gelsemine, vincadifformine, isoreserpiline, aricine, isoreserpinine, and ajmaline have been shown to derive from strictosidine (data are also included for ajmalicine, for catharanthine, and for vindoline which had been reported earlier). 

The indolic nitrogen is the active redox center of indoles, due to its lone pair of electrons [101,102]. Indeed, if the oxygen replaces the nitrogen in the indolic ring, the antioxidant activity of the resulting benzofurane is much lower [47]. Delocalization of this electron pair over the aromatic system seems to be of great importance for antioxidant activity of indole derivatives. 

Biologically important protected and unprotected indole derivatives dissolved in HF were also fluorinated by 18F2. The relatively stable melatonin 53, a neuro-hormone responsible for the biological clock and other brain functions, gave only the 6-[18F]fluoro derivative, but even the more fragile 5-hydroxytryptophan 54, could be fluorinated under these conditions, resulting in a mixture of 4- and 6-[18]fluorohydroxytryptophan (equation 212)371. 

Melatonin is an indole-derived anterior pituitary hormone that causes downstream inhibition of a-MSH-induced melanogenesis. Melatonin is antiamnesic, synchronizes circadian and circannual rhythms and is metabolized to 5-methoxytryptamine. Melatonin acts via GPCRs MT1 and MT2 (which both couple through Gai and cAMP decrease). MT1 may also couple via Gao and Gaq to activate PLC (and hence increase cytosolic Ca2+) and via G Gy activation of PLA2. Melatonin can further interact with nuclear receptor superfamily orphan retinoid receptors RZR/ROR. Melatonin fluctuates with a circadian rhythm and is elevated in blood during the night. Melatonin is accordingly of social importance in relation to shift work and jet-lag. Melatonin and 5-methoxytryptamine occur in some plants (Table 5.8). 

In general, the side chain derivatives of azaindoles undergo reactions analogous to those with indoles. The azagramines and 3-carboxaldehydes are the most useful, leading to many other azalogs of indole derivatives of biological importance. Unfortunately, most of the reactions and compounds involve the more accessible 7-azaindoles, so few comparisons in reactivity differences can be made. 

Tryptophan is probably the indole derivative most widely distributed in nature. It is converted into many other substances of important biological significance. The many materials biogenetically related to tryptophan include nicotinic acid (a vitamin), serotonin (a neurohormone), indoleacetic acid (a phytohormone), some pigments found in the eyes of insects, and a number of alkaloids. 

Electrochemical detectors are based upon the volta-metric oxidation or reduction of separated analytes at a micro- or thin-film electrode. A number of pharmacologically active compounds that are aldehydes, ketones, or quinones (such as doxorubicin), or nitro compounds (such as nitrofurantoin) are amenable to reduction at a mercury or platinum electrode electron-rich indole derivatives and catecholamines can be oxidized at these electrodes. An important condition that must be fulfilled for electrochemical detection to be practicable is that the mobile phase must be capable of conducting an electrical current. This makes electrochemical detection particularly useful in reversed-phase liquid chromatography, where buffered water mixed with one or more organic cosolvents is usually the mobile phase. 

The fact that due to symmetry there is no mixing between the L states in charged perimeters with 4N-I-2 electrons also has consequences for systems derived from these charged perimeters. Even after introducing the perturbation the polarization directions of the L and Lj transitions as well as those of the B, and B2 transitions are mutually perpendicular, and the splitting of the L bands is only small. Important examples are indole derivatives... 

---