Tryptophan, 5-chloro

Of related S3mthetic compounds, one of the most interesting is (+)-6-chloro-tryptophane, which according to Kornfeld [see Chedd, (1974)] is 1000 times sweeter than sucrose all the sweetness resides in the unnatural (+) isomer . 

AC3C - 1-amino-cyclopropanecarboxylic acid Pmp - phosphonomethylphenylalanine 6-Cl-Trp - 6-chloro-tryptophan. 

A parallel study [94] was performed by the same authors on the retention of model compounds (tryptophan, erythro- and t/ireo-P-methyltryptophan, A-carbobenzyloxy-tryptophan, A-(3,5-dinitro-2-pyridyl)-tryptophan, l-[5-chloro-2-(methylamino) phenyl]-l,2,3,4-tetrahydroisoquinoline, and y-phenyl-y-butyrolactone) on a ristocetin A-based CSP, using the three RP, POM, and NP elution systems. Also, in this case, the natural logarithms of the retention factors (In k) of the investigated compounds depended linearly on the inverse of temperature (1 /T). 

L-Tryptophan was used for the synthesis of octahydroindolo[2,3-a]quinol-izines 147 (64CB2463 74CPB2614 81JOC4914), and the tetracyclic system 148 was obtained from a-AAs and 4-chloro-6,7-dihydro-5//-pyrimido[5,4-d][l]benzazepine (93JHC233). 

Some evidence indicates that other drugs with action on the serotonergic system may be associated with efficacy in OCD. Tryptophan, a precursor of serotonin, was shown in a small placebo-controlled study to have an effect size similar to that of the SSRls (S. A. Montgomery et al. 1992). Mianserin, which has 5-HTjq and 5-HT2C receptor affinities, has also been reported in a small placebo-controlled study to be more effective than placebo. This last result raises the possibility that 5-HTjp or 5-HT2C may be the more specific receptors for OCD. The provocation of obsessional symptoms by m-chloro-phenylpiperazine (mCPP), which also has affinities for 5-HT,p and 5-HT2C, reinforces this concept (Zohar et al. 1988a). 

Fig. 7.6 Mechanism of -replacement and /3-elimination reactions with L-serine (X =OH-) or /S-chloro-L-alanine (X- = Cl-). Formation of the Schiff base intermediate with the amino acid ES 1 is followed by removal of the a-proton (H ) and of the leaving group (X-) to form the Schiff base of amino acrylate ES III, the key intermediate in both types of reaction. ES III can be hydrolyzed to pyruvate and NH3 (/3-elimination) or can add the indole cosubstrate (RH) to form the Schiff base of the quinonoid of L-tryptophan ES IV (/3-replacement). Protonation of ES IV leads to release of L-tryptophan. ES IV can also be formed in the reverse direction from L-tryptophan.

At neutral and slightly alkaline pH, N-chlorosuccinimide (NCS) and N-chloro-p-toluenesulfonamide (chloramine-T) oxidize methionine residues in peptides and proteins to methionine sulfoxides (31). Chlor-amine-T is more selective than NCS it does not react with tryptophan whereas NCS does. However both of these reagents react with cysteine. Treating the Ca2+-dependent protein modulator with NCS in the presence of Ca2+ resulted in selective oxidation of methionines 71, 72, 76, and possibly 109 in the modulator sequence with concomitant loss in interaction with cyclic nucleotide phosphodiesterase (32). Methionine residues have been implicated in the activation of cyclic nucleotide phosphodiesterase by the Ca2+-dependent protein modulator. 

The other amino acid reacting with HOC1 is tyrosine. At pH ranging from 3.5 to 6.0, HOC1 reacts with A-acetyltyrosine to produce S -chloro derivative (Fig. 8). If the HOCl/N-acetyltyrosine molar ratio exceeds 10, 3/5/-dichlorotyrosine formation is observed. The chlorotyrosine formation is slow compared to chloramine formation or tryptophan oxidation reaction rate. The optimal conditions for tyrosine... 

A potential for endogenous excitotoxin produced in the CNS via tryptophan metabolism has been localised to microglia.97 Microglia contain indoleamine-2,3-dioxy-genase (the first enzyme in this pathway), which converts tryptophan to kynurenine, and which is induced in microglia and macrophages by IL-1 and infections.98 Inhibitors of quinolinic acid production such as 4-chloro-3-hydroxyanthranilate and ///-nitrobenzylalanine99 100 could probably be of therapeutic value. 

Saito K, Markey SP, Heyes MP (1994) 6-Chloro-D, L-tryptophan, 4-chloro-3-hydroxyyan-thranilate and dexamethasone attenuate quinolinic acid accumulation in brain and bllod following systemic immune activation. Neurosci Lett 178 211-215... 

The recently detected FADH2-dependent halogenases are substrate specific. Tryptophan 7-halogenase catalyzes the chlorination and bromination of d- and L-trypto-phan to 7-chloro- or 7-bromotryptophan, respectively1201. This enzyme also accepts a number of other indole derivatives such as tryptamine, indole-3-acetonitrile, 3-me-thylindole and 5-methylindole as substrates (Fig. 16.9-3a) 43L In addition to indoles, aminophenylpyrrole derivatives are also chlorinated by tryptophan 7-halogenase (Fig. 16.9-3b) 43L... 

Rebeccamycin is a natural product that inhibits DNA topoisomerase I and has been studied as a potential anticancer agent because of the importance of DNA topoisomerase I in cell growth and proliferation. Rebeccamycin analogues are being used in clinical trials for the treatment of neoplastic tumors,renal cell cancer, and leukemia, " rehO is one of the 11 genes in the rebeccamycin biosynthetic cluster. The protein product, RebO, is an L-amino acid oxidase that contains a noncovalently bound FAD. RebO catalyzes the oxidation of 7-chloro-L-tryptophan in an early step in rebeccamycin biosynthesis (Equation (4)). 

Studies in this area were reported as early as 1949 by Lederle chemists [243], who used the Waller synthesis (2,4,5,6-tetraaminopyrimidine, 2,3-dibromo-propionaldehyde and an Af-(4-aminobenzoyl)-a-amino acid or ester) to prepare the alanine, valine, isoleucine, serine, threonine, phenylalanine and tryptophan analogues (VIII.1)-(VIII.7), respectively. Compounds (VIII.2) and (VIII.3) were also treated with CI2 in AcOH to obtain the 3 -chloro derivatives (VIII,8) and (VIII.9). Although the data reported were very scanty, consisting only of activity ratios relative to 10-methylfolic acid in the S.faecium microbioassay, replacement of the glutamate moiety by a-amino monoacids was clearly shown to be an unpromising route to potent antifolates. 

A highly sweet amino acid, monatin (83), was isolated from an African plant, Schlerochiton ilicifolius A. Meeuse (Acanthaceae) [101]. Monatin (83) was rated as being comparable to the synthetic amino acid, 6-chloro-D-tryptophan, which showed a sweetness intensity of 1,300 times that of sucrose. Monatin (83) appears to be the only native plant amino acid with a highly sweet taste to have been discovered. 

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