N-Methyl-leucine

Nitro 2-nitrosO N-rnethylaniline, green prisms from acet/w, mp 165—67° with decompn prepd by the photolysis of N-(2,4-dlnitrophenyl)-N-methyl-leucine (Ref 9)... 

This interpretation was also supported by the spectra of the corresponding N-methyl-leucine derivative in which the H-donor of the selectand was substituted by a methyl group and therefore not available for hydrogen bonding. Both complexes showed a similar spectral behavior as the weak 5-complex of DNB-Leu The C=0 stretch was always shifted from 1725 (uncomplexed autoassociated selector) to 1739 cm (indicative for disrupted H-bonds) in the 5-complex and R-complex as well. These FT-IR data may be regarded as an unequivocal proof for the existence of a stereoselective H-bond between the NH of DNB-Leu and the selector s carbonyl group (Figures 1.10 and 1.11). 

As the amide bond with the fatty acid was more resistant to acid hydrolysis than the peptide bonds, it was possible to isolate N-acyl-N-methyl-leucine by acid hydrolysis which permitted identification of the fifth amino acid. Its isolation was in agreement with the presence of N-methyl protons as indicated by a signal at 3,2 ppm in the H-NMR spectrum of globomycin. The fatty acid was found to be 2-methyl-3-hydroxynonanoic acid, which furnished 3-nonanone by oxidation (see Scheme 7). 

N-methyl leucine at the N terminal end. The N-CH3 and y-CH3 resonances of this terminal residue are useful as monitors of vancomycin behavior. 

A thiazole nucleus or a diketopiperazine is associated with one or two trichloromefhyl groups, and munerous examples of such structures have been found in species of Dysidea. Most of these molecules contain 5,5,5-trichloro-N-mefhyl-leucine or 5,5-dichloro-N-methyl-leucine, which thus appear to be specific a-amino acids in the genus Dysidea, but are not present in peptides or depsipeptides. Figures 19.109 and 19.110 show some examples of these polychlorinated nitrogen derivatives. 

The influence of a large number of oc-amino acids on the values of and k at have been determined. These a-amino acids included glycine, L-valine, L-leucine, L-phenylalanine, L-tyrosine, L-tryptophan, NOrmethyl-L-tryptophan (L-abrine), N-methyl-L-tyrosine, N,N-dimethyl-L-tyrosine and p -me thoxy-N-me thyl -L -phenyl al anine. 

Fig. 13 shows the eSects of pH on the N-terminal N, IV -di[ C]methyl-leucine resonances of glycophorin A, glyco-octapeptide A, and glycophorin B". The titration parameters are listed in Table II. The titration of N, N -di[ C]methylleucine of glycophorin B" resembles that of N N -... 

The cosmopolitan cyanobacterium Microcystis aeruginosa is frequently the major component of freshwater cyanobacterial blooms. These blooms can cause serious water management problems and are occasionally associated with animal poisoning. The aeruginosa toxins are potent lethal peptides which contain three invariant D-amino acids (Ala, erythro-3-methyl Asp, and Glu), two variant L-amino acids, N-methyl dehydroalanine, and a 3 amino acid (1-3). Multiple toxins have been purified from clonal isolates (1,4). The toxic peptide described in this chapter is denoted toxin-LR using the standard one-letter abbreviations for its two variant amino acids, leucine and arginine. 

Cyclosporin (Section 16.1.3) is an undecapeptide that acts as a potent immunosuppressant. Seven of its eleven residues are N-methylated. Its synthesis in solution was carried out by a series of segment condensations)32,33 The didemnins (Section 16.1.4) are isolated from marine organisms known as tunicates. Their therapeutic potential lies in applications as antitumor, antiviral, and immunosuppressant agents. The didemnin family of natural products contains peptidomimetic residues including A,0-dimethyltyrosine-proline and leucine—2-(hydroxyisovaleryl)propionic acid and (4-hydroxy)-2,5-dimethyl-3-oxo-... 

METHYLBUTYL)-, 1,1-DIMETHYLETHYL ESTER, (S)- (5821-45-2), 67, 69 N-tert-Butoxycarbonyl-L-leucine N-methyl-O-methylcarboxamide Carbamic acid, [1-((methoxymethylamino)carbonyl]-3-methylbutyl]-, 1,1 -dimethylethyl ester. (S)- (87694-50-6), 67, 69... 

For the synthesis of epopromycin B, precursor 47 was prepared via the addition of (S)-N-Fmoc-leucinal, 46, to HFIPA, 43, at -55 °C (Scheme 5.10) [67]. The reaction afforded, after methanolysis, two diastereoisomers the syn product 49 was obtained in 70% yield and in 99% ee, and the anti isomer 50 was obtained in 2% yield and in 99% ee. It should be noted that the hexafluoroisopropyl group was converted to the corresponding methyl ester in the alcoholysis step. The major syn isomer 49 was transformed to the epoxy end-product 51. 

Masuko, T., Kashiwagi, K., Kuno, T., Nguyen, N. D., Pahk, A. J., Fukuchi, J., Igarashi, K., and Williams, K. (1999). A regulatory domain (R1-R2) in the amino terminus of the N-methyl-D-aspartate receptor Effects of spermine, protons, and ffenprodil, and structural similarity to bacterial leucine/isoleucine/valine binding protein. Mol. Pharmacol. 55, 957-969. 

Supporting evidence for this proposal was obtained from amino acid analyses which demonstrated that glycine was the only typical or non N-methylated amino acid present in 4ab and Sab. Marfey analysis of the acid hydrolysates of 4ab, Sab and majusculamide C (6) confirmed that 4ab and Sab differed from majusculamide C (6) in possessing an N-methyl-L-alanine residue rather than an L-alanine residue. Moreover, 4ab and Sab contained an N-methyl-L-leucine residue rather than an N-methyl-L-isoleucine residue,... 

N-methyl-N -nitro-N-nitrosoguanidine. Also, a strain that grew well on the leucine analog, 4-azaleucine was isolated. 

Fig. 8. Structure of (a) valinomycin and (5) and enniatins and beauvericin. Hov = a-hydroxy-isovaleric acid and Lac = lactic acid. The N-methyl amino acid for enniatin A is isoleucine enniatin B, valine enniatin C, leucine and beauvericin, phenylalanine.

A novel depsipeptide PF1022A, isolated from a Mycelia sterilia, represents a promising new class of potent anthelmintics [356]. Compound (222) consists of eight residues, four N-methyl-L-leucines, two D-lactates and two 3-phenyl-D-lactates, elaborating a floppy 24-membered ring. In motility assays, it showed potent activity towards Heterakis spumosa (10 7 g/ml) [361] and H.contortus (0.1 pM) [357]. It appears however that it acts as a neurotoxin by paralysing the nematode [358] and its activity is... 

CE3, acyclohexadepsipeptide depsipep-tides) isolated from Streptomyces sp. GE3 collected from a Japanese soil. Building blocks of the rather complex stmcture are, e.g., N-hydroxyalanine, N-methyl-D-leucine, and both enantiomers of piperazic acid. The structure of the open-chain form GE3B was also assigned. GE3 shows strong cytotoxic activity and weak antibacterial activity [T. Agatsuma et al, J. Antibiot. 1997, 50, 704]. 

Amino-acid analogs DL-a-Amino-n-octanoate, D-a-aminophenylacetate, p-amino-DL-phenylalanine, M-benzoyl-DL-leucine, L-a-hydroxyisocaproate, a-ketoisocaproate, N-methyl-DL-leucine [747]... 

Figure 1. Structure of the blue-green algal toxin microcystin-LR. Besides the two variable L-amino acids, leucine and arginine, the microcystin contains three D-amino acids (glutamic acid, alanine and methylaspartic acid) and two unusual amino acids, N-methyl-dehydroalanine (Mdha) and 3-amino-9-methoxy-2,6,8-trimethyl-10-phenyl-deca-4,6-dienoic acid (Adda) (see Ref. 4).

Characteristic structural features of natural cyclosporins include a unique unsatuiated 3 hydroxy-tt-amino acid with a skeleton, (2S, 3R, 4R, 6E)-3-hydroxy-4-methyl-2-methylamino-oct-b-enoic acid, the N-methylation of several of the 11 amino acids, and the presence of D-alanine in the molecule. The individual cyclosporins differ from each other by variation of one or two amino acid constituents. The most frequent diversity occurs in position 2, which can be occupied by L-Z-aminobutyric acid (CyA), L-alanine (CyB), L-threonine (CyC), L-valine (CyD), or L-norvaline (CyG). N-Demethyl analogs are encountered in piositions 1,6, 9,10, and 11. Modifications ar position 5 are illustrated by L-norvaline in CyM and L-leucine in Cy26 instead of L-valine. In position 7, a second... 

L 2 aminobutyric acid can substitute for L-alanine (CyV). N-Methyl-L-leucine in position 4 may be replaced by N-methyl-L isoleucine (Cy29) or by L-valine in CyQ and CyS. Regarding possible biosynthetic pathways, variations at position 1 are of special interest CyF and CyK contain deoxy-MeBmt, whereas N-methyl-L-Z-amino-octanoic acid is found in CyZ, Both building units probably stem from a common precursor of the genuine amino acid (4R) 4 l E) 2 butenyI] 4 fnethYl L-threonine (Bmt). A full exchange of this characteristic structural unit by N-methyl-L-leucine is observed in CyO. At present, positions 3 and 8 containing sarcosine and D-alanine, respectively, are the only conserved building units. 

Studies focusing exclusively on one particular position of the four N-methyl-L-leucines (positions 4, 6, 9, and 10) are not possible because the assay system only provides information about amino acids than can or cannot exchange all of them. In the cyclcKporin series, there are two exceptions due to the availability of natural reference compounds, namely in position 4 (a) CyQ and CyS, in which valine substitutes for leucine and (b) the isoleuctne analog [Melle jCyA. After addition of isoteucine to the CyA incubation mixture to allow the enzyme to incorporate N-methylleucines in positions 6, 9, and 10 simultaneously, [Melle JCyA is formed as major product, indicating that cyclosporin synthetase exhibits a very high affinity for isoleucine only at position 4 (45). It seems that all leucines in cyclosporin can only be replaced by the unbranched hydrophobic amino acids L-norvaline and L-norleucine. Thus, the observed overall substrate specificity for positions 4, 6, 9, and 10 is possibly much higher than for each individual site under consideration. 

In the peptolide SDZ 214-103, leucine occupies the five positions 4, 5, 6, 9. and 10 at three of them (positions 4, 6, and 9), Leu is N-methylated. Therefore, the characterization of substrate specificities of specific leucine sites is even more difficult than that discussed for cyclosporins. Evidently, L-valine and L-norleucine appear to be accepted fi>r all... 

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