5-Active peptide analogues

Fortunately, nature has provided a very useful cysteine derivative, D-penicillamine ( 3, 3-dimethylcysteine), which is readily available and inexpensive (the L-isomer is also available, but is much more expensive). The usefulness of this amino acid in biologically active peptide analogues was shown by Schulz and du Vigneaud1 141 who incorporated it into oxytocin and... 

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. 

Application of the concept of conformational restriction to opioid peptides has produced fruitful results, insofar as peptide analogues and mimetics with interesting opioid activity profiles and high stability against enzymatic... 

Based on the CAAX motif, peptide analogues were designed in which peptide amide bonds are replaced by amine and ether groups [18]. In particular /I-turn mimetic 1 (Fig. 1) inhibits the FTase in vitro with an IC50 value of 1.8 nmol/1 and shows highly specific activity in comparison to inhibition of GGTase I. 

B. Penke, G. Toth, G. Varadi, Analogue and conformational studies on peptides, hormones and other biologically active peptides. Amino Acids Pept. Proteins 34 (2003) 55-148. 

Aminomethylene)-2-phenyl-5(47/)-oxazolone 418 has been converted to 4-(alkylthiomethylene)-2-phenyl-5(47/)-oxazolones 419 by treatment with carbon disulfide and subsequent alkylation. These 4-(alkylthiomethylene) analogues are useful intermediates for biologically active peptides, pharmaceuticals, and plant-protective agents (Scheme 7.136 Table 7.38, Fig. 

The fluorescence quantum yields (tpTrP) of selected, biologically active peptides and peptide analogues containing a single tryptophan residue are presented in Table 1. 

Gould AR, Mabbutt BC, Llewellyn LE, Goss NH, Norton RS. Linear and cyclic peptide analogues of the polypeptide cardiac stimulant anthopleurin-A. H-NMR and biological activity studies. Eur J Biochem 1992 206 641-651. 

The most severe problems exist with peptide ligands, and this is particularly the case for the high-throughput screening of peptide libraries. Once an active peptide has been discovered, it will be necessary to design a suitable non-peptide analogue to avoid the problems of poor absorption and sensitivity to peptidases that confound the direct use of peptides as drugs. It will be necessary to know the conformation of the peptide lead. 

Similar cyclic analogues of substituted phenylalanines 74,75 and histidine 28 have been prepared and incorporated into biologically active peptides. 

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 use of activated esters provides a relatively high degree of synthetic flexibility. Thus, it is possible, for example, not only to synthesize any mixed peptide analogue required, but also to link azaamino acid residues directly in almost any desired number and sequence, enabling the preparation of pure azapeptides. 

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