5-Active peptide analogues synthesis

Current evidence indicates that analgesia mediated by agonist activation of 8-opioid receptors [44] produces less marked side-effects than analgesia mediated by p-opioid receptors [18]. Deltorphins which represent the potent family of opioid peptides originally isolated from frog skin [45] are the most selective 8-opioid receptor peptides. Thus, they have served as parent peptide in the synthesis of numerous 8 active peptide analogues. 

The commercial availability of protected /V-methyl amino acids [(Me)Xaa] of many proteinogenic amino acids (as well as other V-alkyl amino acids), the availability of procedures for the synthesis of protected V-alkyl analogues of all the protein amino acids, and the availability of synthetic procedures for site-selective alkylation during SPPS (see Section 10.1.2.1) allows the alkylation of nearly all peptide bonds in a given parent peptide. The synthesis of a series of V-alkyl peptide analogues based on the sequence of a given bioactive peptide (linear or cyclic) in which each peptide bond is successively alkylated and evaluation of the biological activity of this series will be called herein A-alkyl-scan (for example Me-scan, Et-scan, etc.)... 

The active ester methodology, which is widely used in peptide chemistry, has found only limited application in depsipeptide synthesis. A more vigorous activation of the carboxy component is apparently required to form an ester bond compared to the peptide analogue. Nevertheless, active esters have been utilized for this purpose in combination with some catalyst additives. The first successful attempt in this direction was described by Mazur.1103 The modification of the 4-nitrophenyl ester procedure included addition of 1-10 equivalents of imidazole to the reaction mixture. This accelerated technique presumably involves formation of the highly reactive intermediate imidazolide. The reaction resulted in the preparation of model benzyloxycarbonyl didepsipeptide esters in good yields within several hours at room temperature from 4-nitrophenyl esters of Z-amino acids and the pentamethylbenzyl ester of glycolic acid, while in the absence of imidazole this reaction failed to give any product. 

The synthesis of unnatural amino acids and peptides is of great interest since it offers the possibility to design new biologically active protein analogues. One of the possible interesting transformations is side chain oxidation of amino acids, for which MTO can be used. It is reported that various /V-Boc protected amino acids such as methionine (Met), cysteine (Cys), and tryptophan (Trp) can be oxidized with the MT0/H202 system [108]. 

The bioactive conformation is consistent with the farmacoforic points that are identified through structure activity relationship studies (SAR). SAR studies include the synthesis of many peptide and/or non peptide analogues displaying selectivity for one or another of the receptors and their pharmacologically defined subtypes [19] such as delta 1- and delta2-opioid receprtor subtypes [20]. 

In 1975, Marthell et al. introduced the term phosphonopeptides for peptide analogues in which an aminocarboxylic residue is replaced by an aminophosphonate at any position in the peptide chain [94]. There is an excellent review by P. Kafarski and B. Lejczak [95] devoted to the synthesis of phosphono- and phosphinopeptides. Here, only references connected with the synthesis of biologically active phosphonopeptides using aminophosphonates based on H-hosphonate diesters have been included. 

In a study of nona- and deca-peptide analogues of bradykinin, thiazolidine-4-carboxylic acid was successfully incorporated into the peptide chain in place of proline at position 3 by solid-phase synthesis. The analogues were in general less active than bradykinin. ... 

Much more important than these reactions, however, are the reactions of CDI and its analogues with carboxylic acids, leading to AAacylazoles, from which (by acyl transfer) esters, amides, peptides, hydrazides, hydroxamic acids, as well as anhydrides and various C-acylation products may be obtained. The potential of these and other reactions will be shown in the following chapters. In most of these reactions it is not necessary to isolate the intermediate AAacylazoles. Instead, in the normal procedure the appropriate nucleophile reactant (an alcohol in the ester synthesis, or an amino acid in the peptide synthesis) is added to a solution of an AAacylimidazole, formed by reaction of a carboxylic acid with CDI. Thus, CDI and its analogues offer an especially convenient vehicle for activation of... 

---