Heterodetic peptides

In heterodetic peptides, the ring system is formed from amides and other heteroatom linkages, for example, a disulfide bridge, a thioether or a lactone linkage. The most common nonamide links in heterodetic peptides are the disulfide bonds (found in posterior pituitary hormones such as oxytocin and vasopressin) and the ester (lactone) fnnction. " ... 

Heterodetic peptides, peptides that beside peptide bonds can also contain other bonds, such as ester, disulfide, or thioester bonds. 

Peptides in which all of the covalent linkages between the constituent amino acids are peptide bonds are termed homodetic peptides, whereas those that contain peptide bonds together with other covalent linkages between certain amino acid residues are called heterodetic peptides. Examples of these covalent linkages... 

The cycle of a heterodetic peptide contains only amino acids but the bonds are not all eupeptides . 

However, the term cycHc depsipeptide is often used ia the Hterature to refer to heterodetic homomeric peptide lactones ia which ester bonds to amino acid hydroxyls are present ia the ring. 

Heterodetic cyclic peptides are peptides consisting only of amino acid residues, but the links forming the ring are not solely eupeptide bonds one or more is an isopeptide, disulfide, ester, etc. 

In addition to homodetic cyclic peptides, chemical ligation methods have been developed that lead to heterodetic cyclic peptides containing thiazolidine. 158-161 ... 

In the following discussion a selection of optimized procedures is presented for the synthesis on solid support of homodetic monocyclic and bicyclic as well as mixed homodetic/ heterodetic bicyclic peptides that contain at least one lactam ring, whereas heterodetic cyclic peptides containing other than amide bonds or peptidomimetics are not discussed here because of their unlimited diversity. 

Both homodetic and heterodetic cyclizations via the peptide termini and/or the sequence-encoded side-chain functionalities limits the variability in ring size and chemistry. In order to enhance the diversity in these terms, the concept of extended and reverse-extended lactam ring (also called branched peptides) was introduced.1415 As shown in Scheme 19, this necessitates an additional spacer consisting of an amino acid residue or of a peptide chain inserted between the two side-chain functionalities involved in cyclization. Depending upon the parallel or antiparallel orientation of the inserted spacer, the resulting constructs are termed extended (branched) and reverse-extended peptides.[415]... 

The bicyclic peptides that have been synthesized with at least one lactam ring correspond to the structures shown in Scheme 22, and examples of such syntheses of homodetic or mixed homodetic/heterodetic structures are listed in Table 12. For bicyclic or polycyclic cystine peptides see Sections 6.1 and 6.2. In the ring structures of types I-III both rings derive from side-chain-to-side-chain cyclizations. In the structures of types IV-VI an cofunctionalized amino acid is employed as bridgehead. This can be linked directly to three... 

Similarly, the mixed homodetic/heterodetic bicyclic structures containing a disulfide bridge are preferably produced as monocyclic compounds that are then typically oxidized in solution adopting standard procedures as described in Section 6.1.1 (Scheme 23, path Bl). If even disulfide formation is performed on resin by the procedures reported in Section 6.1.2, an additional level of selective protection is required for the cysteine thiol functions. The synthetic paths Bl and B2 are also applicable for the synthesis of type II and III bicyclic peptides, independent of whether only lactam bridges are produced or mixtures of lactam/ disulfide bridges. 

For the synthesis of the heterodet cyclic depsipeptides, the acid chloride which had been prepared after the removal of the iV-protecting groups was most used. Recently, a mixture of acetylchlqride and acetylimidazole has been used for the cyclization of actinomycin acid to actinomycin Ci . Heterocyclic peptides containing disulphide rings have been cyclized by oxidation of the corresponding disulphydryl compounds . 

Amatoxins, heterodetic bicyclic 8-peptides from Amanita species, but also detected in Galerina and Lepiota species, which are responsible for the fatal intoxications by the mentioned toadstools. The toxic peptides are readily absorbed by the intestine, and in humans the lethal dose of amatoxin is 0.1 mg kg body weight, or even lower. The gut cells of humans seem to be the first cells affected, and the intestinal phase begins about 9 h after... 

Heterodetic cyclic peptides in which a disulfide bridge takes part in ring formation are obatined by the methods already discussed in connection with the construction of disulfide bridges between separate chains. Of course the dilution principle must be followed in order to diminish the extent of bimolec-ular reactions. 

P. which contain only amino acid residues are called homomeric P., whereas P. with non-amino acid constituents are known as heteromeric P. Each of these classes is further subdivided into homodetic P., which contain only peptide bonds, and heterodetic P, which contain other bonds, e.g. ester, thioether or disulfide. Heterodetic P. possessing one or more ester bonds as hetero link are called Depsipeptides (see). The classification of depsipeptides does not accord entirely with the homomeric/heteromeric system it has arisen from the fact that the synthesis of these peptides presents rather special problems. There are two types of homomeric depsipeptides O-peptides contain ester-linked hydroxyamino acids, and they may be linear or cyclic (i. e. lactones) in S-peptides or thiodepsipep-tides, the mercapto group of a cysteine residue is acy-lated with an amino acid. Heteromeric depsipeptides contain hydroxy acids as the hetero component, and they are also known as peptolides. P. with non-amino... 

Val-CO-O-Thr-OH Heterodetic cyclic branched peptide (peptide lactone)... 

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