Peptides stereoisomerization

R. Haubner, D. Finsinger, H. Kessler, Stereoisomeric peptide libraries and peptido-mimetics for designing selective inhibitors of the alpha-v-beta-3 integrin for a new cancer therapy, Angew. Chem. Int. Ed. Engl. (1997) 1374-1389. 

Each of the scaffolds reported in Scheme 24 can be used for the production of a stereo-isomeric sublibrary based on the appropriate peptide sequence. For example, with the sequence A-B-C-D-E and scaffold (1) two types of stereoisomeric sublibraries can be prepared. One type includes the sublibraries A and B of Scheme 26 in which within a given sequence the configuration of each residue is successively inverted thus, retaining the identical connectivity as in the parent linear peptide. In the second type 265 of sublibraries C and D (Scheme 26) the direction of the amide bond is inverted and hence the connectivity is not maintained. In most members of these sublibraries the overall conformation of the scaffold is maintained and therefore these components constitute stereoisomeric sublibraries of the parent library. Conversely, by introducing amide bond surrogates such as reduced amide bonds1465 or thioamide bonds 260,466 the conformation of the scaffolds are changed and their conformational flexibility enhanced. 

Bioactive sequences of up to six amino acid residues known to assume (1- or "/-turns in the bioactive conformation are suitable for such libraries. If the sequence is short, residues have to be added in a manner to retain the desired physicochemical properties of the peptide (e.g., to short polar active sequences hydrophobic residues are preferentially added and vice versa). The choice of the scaffold depends on the number of structure-inducing amino acids such as Gly or Pro present in the native sequence. In absence of such residues scaffolds (1) or (4) (Scheme 24) are selected, whereas if Gly or Pro is present alternative scaffolds can be considered. Then the components of the four stereoisomeric sublibraries of Scheme 26 (or their equivalents if other scaffolds are chosen) are synthesized according to procedures described in the preceding sections. 

Nearly all biological compounds with a chiral center occur naturally in only one stereoisomeric form, either d or L. The amino acid residues in protein molecules are exclusively L stereoisomers. D-Amino acid residues have been found only in a few, generally small peptides, including some peptides of bacterial cell walls and certain peptide antibiotics. 

Another Fischer achievement was the synthesis of small peptides via the condensation of amino acids. Fischer suggested that there was a common linkage that held pairs of amino acids together in all proteins—the peptide bond. He understood that proteins were tremendously complex, owing to the large number of constituents and the fact of stereoisomerism. By 1916 Fischer had synthesized and characterized 100 peptides, but knew they represented a tiny fraction of what was possible, see also Amino Acid Carbohydrates Isomerism van t Hoff, Jacobus. 

Fig. 6.30. Mechanism of the stereoisomerization of an N-protected amino acid chloride under the conditions of a peptide synthesis. The red reaction arrows stand for the steps of the racemization.

One problem that remains is the mode of interaction between the sweet peptides and the receptor site. Despite a great number of studies, the mechanism of action of sweet stimuli on the receptor is not well known. Stereoisomerism can be responsible for differences in taste responses, and space-filling properties are also very important. These facts suggest that the receptor site exists in a three-dimensional structure. In this connection, the sense of sweet taste is subject to the "lock and key" of biological activity. 

Later, when it was recognized that stereoselective syntheses could also be accomplished, syntheses of stereoisomeric a-amino acid and peptide derivatives by suitable U-4CRs were attempted.b45] As such reactions require the use of chiral components, the products of U-4CRs must contain selectively removable chiral auxiliary groups. Consequently, the search for such groups has become one of the key areas of contemporary U-4CR chemistry. Whilst not all problems have optimally been solved, it is nevertheless presently possible to synthesize many types of a-amino acid derivatives by the U-4CR. 

Occasionally, it is advantageous to form a peptide derivative by a U-4CR so that N- and C-protected a-amino acids are used as 2A and 3A with a new connected C-N bond of the other functional groups of their product 18A. The component 1A of such a U-4CR must be selected so that 18A can be converted into 31B without any cleavage or stereoisomerization, and 31B can be obtained with ease as a pure product. 

P-Ami no acids, although of less importance than their oc-analogues, are also present in peptides and different heterocycles, and their free forms and derivatives exhibit interesting pharmacological effects [1]. A number of syntheses and transformations have been performed on their stereoisomeric alicyclic analogues (e.g. 1-3). Until recently, the investigations were mainly of academic interest since no naturally-occurring compounds were known. 

Scheme 20 yielded the target 3 -phosphono-L-tyrosine as its trimethyl ester benzyl ether (194). The stereoisomeric composition of the product was determined by the generation of the diastereoisomeric peptides (195), the h.p.l.c. of which indicated the S,S)/ R S) ratio as 87.4 12.6. ... 

Neopetrosiamides A and B are two complex dia-stereoisomeric tricydic peptides isolated from a Neopetrosia sp. collected in Papua New Guinea. Both inhibit amoeboid invasion of human tumor cells (Williams et al, 2005a). 

The terminology introduced by Linderstrom-Lang (1952) is generally used to define three levels of protein structure designated as primary, secondary, and tertiary structure. The primary structure is defined by the amino add sequence of the polypeptide chain which is maintained by covalent links called the peptide bonds and does not describe the spatial arrangement. However, stereoisomerism (l and D forms) is included in this level of structure. 

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