Depsipep tides

The best known groups of the cyclic compounds concerned are the depsipep-tides (e.g., valinomycin), the macrotetrolides (e.g., nonactin and monactin) and the synthetic polyethers (crown ethers) they are used at concentrations of 10 4-10 7 M, e.g., in decane. Valinomycin membranes show a K+ selectivity of... 

H Kunz, H-H Bechtolsheimer. Synthesis of sterically hindered peptides and depsipep-tides by an acid chloride method with 2-phosphonioethoxycarbonyl-(Peoc)-amino acids and hydroxy acids. Liebigs Ann Chem 2068, 1982. 

A number of methods for the synthesis of piperazic acid (7) and related derivatives are currently available as a result of growing interest in natural product chemistry and in their potential in medicinal chemistry. Their chemistry and conformational properties have been comprehensively reviewed. 2451 Racemic piperazic acid is obtained by condensation of penta-2,4-dienoic acid with phthalazinedione and subsequent reductive deprotection of the resulting A,A -bis(phthaloyl)-l,2,3,6-tetrahydropyridazine-3-carboxylic acid.12431 Resolution of racemic piperazic acid is achieved by fractional crystallization of the ephedrine salt of Nl-(benzyloxycarbonyl)piperazic acid from ethyl acetate. 246,2471 A typical route to enantiomerically pure (3S)-piperazic acid 56 starts from chiral 2-amino-5-hydroxyvaleric acid 55 as shown in Scheme 12.1248 Convenient stereoselective syntheses have been reported for 5-hydroxy- and 5-chloropiperazic acids as important constituents of natural cyclic peptides and depsipep-tides.1249,2521... 

M Adam, C Damblon, B Plaitin, L Christiaens, JM Frere. Chromogenic depsipep-tide substrates for 3-lactamases and penicillin-sensitive DD-peptidases. Biochem J 270 525-529, 1990. 

Flavopiridol enhances depsipep-tide-mediated apoptosis in lung and esophageal cancer cells via activation of mitochondrial death signal pathways. Proc. Am. Assoc. Cancer Res. 43 350 (Abstr.)... 

However, some other depsipeptides require additional tools. Many depsipep-tides of natural origin possess complex architectures such a cyclic or a bicyclic skeleton and may include unnatural or N-methylated amino acids in their structure. In these cases, a manual synthesis combined with careful optimization of each step is required. In this regard, syntheses of callipeltin B [171] and oxathio-coraline [172] have recently been described. 

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]. 

At the end of this chapter, cyclic peptides will be mentioned one of them (a mixture) being indeed the first antibiotic peptide ever isolated actinomycin from cultures of Streptomyces antibioticus by Waksman and Woodruff in 1940. The different actinomycins are orange-red peptides all containing the same chromo-phore, an aminophenoxazinone dicarboxylic acid, whose carboxyl groups are connected via the amino group of threonine with two identical cyclic depsipep-tide rings consisting of five amino acids. In Fig. 28 the cyclic part of actinomycin C3 is depicted as determined by H. Brockmann (Plate 13) and associates, who in the fifties contributed most to the analytical and synthetic chemistry of this class of compounds. 

Paravidino, M., Scheffelaar, R., Schmitz, R. R, de Kanter, F. J. J., Groen, M. B., Ruijter, E., Orru, R. V. A. (2007). A flexible six-component reaction to access constrained depsipep-tides based on a dihydropyridinone core. Journal of Organic Chemistry, 72,10239-10242. 

Carpino LA, Krause E, Sferdean CD, Schumaim M, Fabian H, Bienert M, Beyermann M (2004) Synthesis of difficult peptide sequences application of a depsipep-tide technique to the Jung-Redemann 10- and 26-mers and the amyloid peptide Ab(l-42). Tetrahedron Lett 45 7519-7523... 

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