Tryptophan analogues

The appearance of the 2-(indol-3yl)ethylamine (tryptamine) unit in both tryptophan-derived natural products and in synthetic materials having potential pharmacological activity has generated a great deal of interest in the synthesis of such compounds. Several procedures which involve either direct 3-alkylation or tandem 3-functionalization/modification have been developed. Similarly, methodology applicable to preparation of tryptophan analogues has been widely explored. 

Reaction of methyl 2-quinolylacetate with 2-A-trifluoroacetylamino-5-bromo-4-oxonorvaline methyl ester gave 103, a tryptophan analogue of pyrroloquinoline (96KG1510). 

Torok, G. et al.. Enantiomeric high-performance liquid chromatographic separation of -substituted tryptophan analogues, Chromatographia, 51, SI65, 2000. 

Selected tryptophan syntheses will first be described because tryptophan is easily converted into its decarboxylation product tryptamine. Major emphasis will be placed on tryptophan analogues with a variety of substitution patterns at the aromatic ring system. These derivatives could be of significance for producing new tryptophan derived alkaloids. 

Two recently published procedures should be highlighted. Development of simple and scalable one-step biotransformation of 4.5.6.7-halogenated (F, Cl, Br) and methylated indoles into the appropriate tryptophan analogues (Fig. 3) is based on 3-days incubation of a bacterial lysate together with L-serine at 37°C [63]. 

Another possibility is that endogenous epileptogenic compounds may be produced in the brain of the epileptic patient. Both tetrahydroisoquinolines and beta-carbolines have been detected in the human brain, as has the tryptophan analogue quinolinic acid, which all have convulsant and excitotoxic properties. The enzymes that synthesize quinolinic acid have also been identified in human brain tissue. 

The analogues of serine and tyrosine were prepared from suitably protected hydroxy aldehydes and the tryptophan analogue from indolepyruvic acid. A wide selection of other o -aminophosphonous acids was also prepared from aliphatic, aromatic and heterocyclic aldehydes and aliphatic ketones. 

Recently, three TPO models have been reported bis (salicylidene)ethylenediaminato cobalt(II) [Co(salen)] in MeOH (14), cobalt(II)tetraphenylporphyrin (CoTPP) (25) in DMF, and manganese phthalocyanine (Mn-Pc) in DMF (16). These models have been reported as having the TPO-mimic function of oxygenating skatole, a tryptophan analogue, to form 2-formamidoacetophenone (FA). However, one of the most critical problems for these models is the lack of structural similarity between the TPO active site (heme) and these models. The structure of these models is not similar to the heme in TPO with respect to the central metal and/or the ligand. Furthermore, Fe(salen) does not possess the TPO-mimic function (14). 

Kwon I, Tirrell DA. Site-specific incorporation of tryptophan analogues into recombinant proteins in bacterial cells. J. Am. Chem. Soc. 2007 129 10431-10437. 

Treatment of the amine 14 (R = H) with sodium ethylacetamido-malonate gave the tryptophan analogue 17 on acid hydrolysis. Decarboxylation of the amino acid 17 in acetophenone gave the Schiff base 18, which was hydrolyzed by acid to the tryptamine analogue 19. Methylation of the amine 14 (R = H) with methyl iodide gave the quaternary salt 20,... 

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. 

Hamill, R. L., Elander, R. P., Mabe, J. A., and Gorman, M. (1970) Metabolism of tryptophan by Pseudomonas aureofaciens III. Production of substituted pyrrolnitrins from tryptophan analogues. Appl Microbiol 19,721—725. 

Wong C-Y, Eftink M R (1997). Biosynthetic incorporation of tryptophan analogues into staphylococcal nuclease Effect of 5-hydroxytryptophan and 7-azatryptophan on structure and stability. Protein Sci. 6 689-697. 

In a similar manner, another antimigraine drug candidate 1 has been prepared using a silylalkyne [86]. Here it was found that 2,4,6-trimercapto-s-triazine provides a very useful way to remove residual palladium. A number of tryptophan analogues have been prepared using this same silylalkyne chemistry, followed by protodesilylation [87-93] (Eq.43). 

Scheme 2. Structures of the various tryptophan analogues referred to in this work.

The cell-free synthesis of strictosidine (79) and cathenamine (82) has been further explored, and the conditions under which these key compounds are formed have been optimized. Strains from C. roseus suspension cultures that were resistant to inhibition of their growth by various tryptophan analogues have been selected. The free tryptophan level in cells of these strains could be 30—40 times higher than in normal cells. Tryptophan at this level did not induce tryptophan decarboxylase, nor the production of alkaloids. It is to be noted, however, that stimulation of alkaloid production by tryptophan and tryptamine ° in cultures of normal cells has been reported. In the case of tryptamine the two most prominent metabolites were A/ -acetyltryptamine and JVN-dimethyltrypt-amine. 

Ryu, JW, HS Chang, YK Ko, JC Woo, DW Koo and DW Kim (1999). Direct chiral separation of tryptophan analogues using heptakis(3-0-Methyl)-beta-cyclodextrin-bonded stationary phase in reversed-phase liquid chromatography. Microchemical Journal, 63(1). 

Close analogues of the amino acid tryptophan can be inserted into a polypeptide simply by adding the desired amino acid to the medium in which a tryptophan-deficient auxotroph of E.coli is cultured. However, this approach cannot be used in single molecule studies as these tryptophan analogues (which can be covalently attached to tRNA P and hence incorporated into the nascent chain) still have unsuitable photophysical properties. 

Fluorescence based structural analysis of tryptophan analogue— AMP formation in single tryptophan mutants of Bacillus stearothermophUus tryptophanyl-tRNA synthetase. Biochemistry 42 (2003) 14994-15002. 

Sasse F, Buchholz F, Berlin J (1983) Site of action of growth inhibitory tryptophan analogues in Catharanlkus roseus cell suspension cultures. Zeitschrift fur Naturforschung 38C 910-915... 

Meech, S. R Phillips, D. Time-Resolved Fluorescence Spectroscopy of Tryptophan Analogues in Lipid Bilayers. Unpublished results 1980 Memming, R. Z. Phys. Chem. 28,168 (1961)... 

Evidence obtained with radioisotopically labeled tryptophan as well as with certain tryptophan analogues have established that tryptophan is a precursor of the actinomycin chromophore (Katz, 196O Sivak, Meloni, Nobili and Katz, 1962 Sivak and Katz, I962). In experiments with benzene ring-labeled tryptophan it was shown that the C-label of the amino acid was efficiently (11.7%) and preferentially incorporated into the phenoxazinone moiety of actinomycin (Table 3). The chromophore derivatives, actinocinin and desaminoactinocylthreonine dimethyl ester, obtained from actinomycin by acid hydrolysis (Brockmann and Grone,... 

Ilisz I, Fodor G, Berkecz R, Ivanyi R, Szente L, Peter A. Enantioseparation of (3-substituted tryptophan analogues with modified cyclodextrins by capillary zone electrophoresis. J. Chromatogr. A 2009 1216 3360-3365. 

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