Cystine derivatives

Considerable amounts of glutamic acid, glycine, and alanine, as well as smaller quantities of aspartic acid, serine, threonine, basic amino acids, leucine, phenylalanine, and cystine have been demonstrated in a total hydrolyzate of the nondiffusible fraction by Boulanger et al. (BIO). Using Deacidite resin, they separated this material into two polypeptide fractions, acid and alkaline, and found that glutamic acid, aspartic acid, leucine, and certain cystine derivatives were the chief constituents of the former, whereas the latter contained considerable amounts of glycine, basic amino acids, and alanine. 

For the synthesis of double-stranded symmetrical and unsymmetrical monocystine peptides the formation of an intermolecular disulfide bridge is required. For homodimerization of cysteine peptides all the methods discussed in Section 6.1.1 can be applied taking into account the reactivity of the different oxidative agents toward sensitive amino acid residues present in the peptide sequences. Synthetic approaches based on the direct use of suitable cystine derivatives can be envisaged, at least for small-size peptides since disproportionation would in all cases retain the homodimeric structure 241... 

Side Products in Peptide Synthesis with Cystine Derivatives... 

The standard approach to the synthesis of peptides containing disulfide bridges is to use S-protected cysteine derivatives for chain elongation and then subsequently form the disulfide by oxidation of the final S-protected or S-unprotected cysteine peptides (Section 6.1.1). The alternative approach, based on the use of suitably protected symmetrical or unsymmetrical cystine derivatives for the synthesis of disulfide bridged homo-, or heterodimers, besides exhibiting the difficulties discussed in Section 6.1.3, was recently found to generate under... 

Critical appraisal of the method, 23,26 using attempts to synthesize nonsymmetrically substituted lanthionines, resulted in rearrangement of the products, presumably due to phosphine-catalyzed disproportionation of the unsymmetrical disulfides. This reaction should proceed more rapidly than the desulfurization process and is thought to occur because sulfur extrusion takes place via a reversible reaction by recombination of ionic intermediates (Scheme 3). 21-22-24 Thus, the reaction of nonsymmetrical cystine derivatives results in the formation of a mixture of three different lanthionines. 

A further approach for the synthesis of nonsymmetrically protected lanthionines is the conversion of thiosulfinates of symmetrically protected cystine derivatives into nonsymmetrically protected cystines via a reaction with a cysteine derivative and subsequently the conversion of the resulting unsymmetrically protected cystine into the nonsymmetrically protected lanthionines with a tris(dialkylamino)phosphineJ26l The oxidation of the symmetrically protected cystine, e.g. A,AT-bis(benzyloxycarbonyl)-L-cystine diethyl ester, of one stereochemical configuration to the thiosulfinate with m-chloroperoxybenzoic acid is essentially quantitative. The nonsymmetrical cystine is then formed in a subsequent step by the addition of the /V-/er/-butoxycarbonyl-L-cysteine tert-butyl ester derivative to give N-Z-N -Boc-L-cystine ethyl ferf-butyl diester. The desired 2f ,6f -lanthionine is then formed in the presence of P(NEt2)3 in yields of >50%. 

The one-pot synthesis of lanthionines starting from thiosulfinates and cysteines and subsequent addition of tris(diethylamino)phosphine was not successful. Moreover, with this method based on L-cystine derivatives only L-lanthionines have been synthesized. In this context it is worth noting, that alternative and possibly more efficient methods can be applied for the synthesis of the unsymmetrically protected cystines as intermediates (Section 6.1.3). 

In contrast to the syntheses described above, which all start from cystine derivatives to form lanthionine, the lanthionine syntheses in this section all start from a protected cysteine as the nucleophilic precursor, which is then allowed to react with any of a variety of different substrates. These subsequent reactions are the Michael addition with dehydroalanine, the nucleophilic substitution of halo amino acids, or the ring-opening reaction of serine p-lactones and aziridines, respectively. However, it must be emphasized that the Michael... 

The synthesis of four out of eight possible stereoisomers of 3-methyllanthionine [(25,35,67 ), (25,37 ,67 ), (25,35,65), (25,37 ,65)] has been achieved using the reaction of Z-protected 3-methyl-D-cysteine with d- or L-3-chloroalanine in yields of 35—53% J64 The methyl-D-cys-teine stereoisomers were obtained by two routes. Firstly from (25,35)-threonine via O-tosylation and subsequent inversion of configuration by nucleophilic attack with thiobenzoic acid. The resulting derivative was debenzoylated and oxidized to the respective cystine derivative prior to the reduction with Zn/HCl to give the eryt/u-o-3-methyl-D-cysteine... 

The use of Trt-protected 3-iodoalanines for lanthionine synthesis is also a highly promising method for the synthesis of 3-methyl- and 3,3-dimethyllanthionines. 40 This method is based on the use of A-trityl-3-iodoalanine benzyl ester (54) and the symmetrically protected bis(Boc)-cystine-derivative dimethyl esters derived from L-t/treo-3-methylcysteine and d-penicillamine. Yields of the respective lanthionine derivatives are >80% however, enantiomeric excesses have not been determined for the 3-substituted lanthionines (Scheme 18). 

Figure 3-14 The spectra of the first electronic transitions of the N-acetyl derivatives of the ethyl esters of phenylalanine, tyrosine, and tryptophan together with that of the dimethyl ester of cystine in methanol at 25°C. The spectra for the Tyr, Phe, and cystine derivatives have been multiplied by the factors given on the graph.272...

In addition to enzymatic hydrolysis of natural lipids in polymeric membranes as discussed in chapter 4.2.2., other methods have been applied to trigger the release of vesicle-entrapped compounds as depicted in Fig. 37. Based on the investigations of phase-separated and only partially polymerized mixed liposomes 101, methods to uncork polymeric vesicles have been developed. One specific approach makes use of cleavable lipids such as the cystine derivative (63). From this fluorocarbon lipid mixed liposomes with the polymerizable dienoic acid-containing sulfolipid (58) were prepared in a molar ratio of 1 9 101115>. After polymerization of the matrix forming sulfolipids, stable spherically shaped vesicles are obtained as demonstrated in Fig. 54 by scanning electron microscopy 114>. 

The synthesis of 3-alkyl-substituted 1,2-thiazetidine 1,1-dioxides starts by transformation of the amino acids L-Val, L-Leu, L-Ile, and L-Phe into amino alcohols. These ate converted via the bromides to the corresponding thiols 161. Immediate oxidative chlorination affords either sulfonyl chloride hydrochlorides or sulfonic acids 162 which are transformed into the parent /3-sultams 163 <2004HCA90>. Similarly, L-cystine derivatives 164 have also been transformed into the parent /3-sultams 165 by oxidative chlorination followed by cyclization (Scheme 50) C1997LA1261, 2004HCA90>. 

Treatment of cystine derivatives 222 with Zn/AcOH led to S-S bond cleavage and ring closure of intermediate thiols into lactones 223a-d in moderate yields (Equation 23) <2004S3029>. 

Scheme 3 Asymmetric Cystine Derivatives Suitable for the Synthesis of Asymmetric Cystine Peptides ...

Two of the three conserved a helices are fastened together by disulfide bridges to form a highly stable substructure that contributes many of the active site residues. Four (class III), five (class I), or six (class II) of the disulfide bridges found in sPLAgS incorporate half-cystines derived from this substructure. Conserved side chains arising from these helices assist in the coordination of the primary calcium ion (Asp-49/35), form the deeper contours of the hydrophobic channel (Cys-45, Ala-102, Ala-103, Phe-106), and create the catalytic network (His-48/34, Asp-99/64, Tyr-52/87). 

Bis-V-tert-hutyloxycarhonyl-L-cystine, [10389-65-8] M 440.5, m 144.5-145 , [a] g -133.2 (c 1, MeOH), 2.9. Crystallise the cystine derivative from EtOAc by adding hexane [Ferraro... 

A similar synthetic scheme was adopted by Nadel [13] to prepare isothiazolones 34 and 35 from L-cystine derivatives transformed into the corresponding cystine fozs-N-(methylamides) 33a-c (Et0C02Cl, TEA in CH2CI2 then MeNH2/H20, 69- 73%) (Scheme 10). As reported in Table 1, several parameters were evaluated in order to find the best reaction conditions to produce the different isothiazolone derivatives 34 (43-63%) or 35 (52-66%). As by-products, the polyhalogenated compounds 36 and 36 (not separable) were formed in some instances. Finally, the deprotection of the amino group... 

JA2393>. The nucleophilic attack on cystine-derived chiral 4-amino-1,2-oxathiolane 2-oxides (57) by alkyllithiums takes place at the sulfur atom with inversion of configuration to afford (58) (Equation (4)) <81JOC5408>. 

The chiroptical properties of a number of sulfur-containing amino acids (cysteine or cystine derivatives, such as lanthionine, cystathionine, allo-cystathionine, djenkolic acid, felinine, and S-alkylcysteines) have been described (Coleman and Blout, 1968 Casey and Martin, 1972 Jung et aL, 1973 Takagi et al, 1973 Ottnad et ai, 1975) and correlated with the chiroptical characteristics of the parent compounds. 

E. Brand, M. Sandberg, The labihty of the sulfur in cystine derivatives and its possible bearing on the constitution of insuUn. J. Biol. Chem. 70 381-395 (1926)... 

A soln. of N-carbobenzoxy-S-benzylthiomethyl-L-cysteinylglycine in ca. 98%-formic acid added with swirling to an aq. partial suspension of mercuric acetate so that a clear soln. is obtained, after 15 min. at room temp, ethanedithiol added to minimize thiazolidine ring formation, after 15 min. HgS passed in, the precipitated mercuric sulfide removed by filtration, and the product isolated as the cystine derivative di (carbobenzoxy)-L-cystinyldiglycine. Y 79%. F. e. s. P. J. E. Brownlee et al., Soc. 1964, 3832. 

Synthesis of the cystine derivative of the insulin tetrapeptide Ae-e has been described by Zahn and colleagues and its reactivity toward boron trifluoride-glacial acetic acid, hydrazine, and triethylamine has been evaluated. ... 

Grignard reagents behave similarly,and a thioborane gives an un-symmetrical sulphide with a sulphenate ester. Tris(diethylamino)-phosphine converts cystine derivatives into corresponding lanthionines [NH2 CH(C02H) CH2]2S, 2 and the disulphide formed between penicillin sulphoxide and Bu SH (36 fine s in place of Me at S) forms the ethyl sulphide (36 Et in place of Me at S) by treatment with triethylphosphine. ... 

DMPC also a cystine derivative with fluorocarbon chains has been used to form mixed... 

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