Sulfur-containing cyclic peptide

Fig. 7 Sulfur-containing cyclic peptides as prodrugs for HDAC inhibition. (Kyushu Institute of Technology)...

The sulfur extrusion method 21 has been extensively investigated for the synthesis of threo-3-methyllanthionine 25 however, in this case desulfurization was not used to generate the amino acid (either in free or protected form), but rather to form different sulfide-bridged cyclic peptides as precursors for the total synthesis of nisin (3). Development of synthetic methods in this area was particularly important in respect to the synthesis of nisin, since this lantibiotic contains four // eo-3-methyllanthionine residues. The synthesis proceeded from a protected f/zreo-3-methyl-D-cysteine in the N-terminal position and L-cysteine in the C-terminal position. 

The biosynthesis 237,5381 involves enzymatic dehydration of serine and threonine residues in a manner similar to the formation of thiazoles and dihydrothiazoles vide supra) with or without subsequent oxidation to yield the 2-(l-aminoalkyl)oxazole-4-carboxylic acid and 2-(l-aminoalkyl)dihydrooxazole-4-carboxylic acid shown in Scheme 38. These cyclic peptides display interesting physiological properties such as cytotoxicity/541, 569,5831 antitumor activities, or antineoplastic effects/523,5291 but as for the sulfur-containing compounds the mechanism of action is not yet understood despite extensive SAR studies. 515,521,540,5431... 

Cyclic peptides 248 containing cysteine units can lose one sulfur atom by interaction with hexaethyl phosphoric acid triamide, affording ring-contracted structures 249 (83BCJ2044, 83MI2 86BCJ2505) (Scheme 67). 

The poisonous components of the most deadly mushroom Amanita phalloides (the Death Cap) are bicyclic heptapeptides which have an additional covalent bond that connects the ( -sulfur atom of an l-cysteine residue with the carbon atom in position 2 of the indole ring of the L-tryptophan. Phalloidin (or phalloidine) is the most abundant member of a whole family of related cyclic heptapeptides called phallotoxins (for a review, see Wieland1 1). These poisonous peptides, therefore, contain a cross-linking moiety consisting of L-tryptophan coupled to L-cysteine, designated tryptathionine (1), alternatively called 5-(trypto-phan-2-yl)cysteine or 2-(L-3-alanylsulfenyl)-L-tryptophan (Scheme 1). 

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