Peptide cyclic peptidomimetics

This review will focus on the use of MCR approaches to cyclic peptides, cyclic peptidomimetics, or cyclic pseudopeptides, including small or medium-sized heterocycles as mimics of peptide motifs and macrocycles with amino acid or peptide moieties. 

A similar approach has been described by the same authors for the synthesis of related cyclic peptidomimetics [44]. A set often nucleophiles was employed for the substitution of the chlorine atom of the cyclic triazinyl-peptide bound to the cellulose membrane. By virtue of the aforementioned rate enhancement effects for nucleophilic substitution of the solid-supported monochlorotriazines, these reactions could be rapidly carried out by microwave heating. All products were obtained in high purity, enabling systematic modification of the molecular properties of the cyclic peptidomimetics. 

Several groups tried to access medium-sized rings (ca. 8-12 membered) with peptide-like moieties. Most prominent is the I-MCR/RCM strategy [15, 16], As shown in Scheme 11. 12-Memhered cyclic peptidomimetics were reported hy Oikawa and co-workers who used initial Ugi-4CRs performed in excellent yields, followed hy functionalization of the resulting Ugi-platform to introduce the desired alkene functionalities [65]. RCM with the second generation Hoveyda-Gruhhs... 

The field of peptide synthesis is never far removed from the study of natural products, many of which exhibit peptide and peptidomimetic structures. It is fitting that this treatise be concluded with a section on the synthesis of key peptide-based natural products. Section 16 commences with the synthesis of bacitracin)30 a cyclic peptide with antibiotic properties. The synthesis of this target structure is carried out in solution and by solid-phase chemistry. The molecule contains a lactam-bridged cyclic heptapeptide with a pendent tripeptide (Section 16.1.1). An elegant route to the synthesis of the thiazoline building block is included. 

The introduction of conformational restrictions into flexible active molecules is a well-known strategy for trying to increase their potency and/or selectivity toward their biological targets.1 Several methods have been used for constraining flexible molecules. Cyclic derivatives of hnear peptides or peptidomimetics can thus be prepared by reactions involving side-chain... 

Hebach and Kazmaier reported the synthesis of cyclic peptidomimetics containing an alkylated amino acid via Ugi-4CR of N-terminal-protected aloc-amino acids, allyl isocyanoacetate, and chiral amines in trifluoroethanol. Allylic esters of tripeptides 193 were obtained in high yields and good stereoselectivity. Metathesis with 5% of Grubbs first-generation catalyst gave 16-membered cyclic peptides 194 in 30-50% yield (Scheme 2.69) [101]. 

Regioselectively addressable functionalized templates (RAFT), oligovalent moieties with chemically distinct functional groups that can be selectively addressed in the preparation of template-associated synthetic proteins (TASP). RAFT are molecular scaffolds that comprise porphyrins, steroids, calixarenes, glycosides, and a variety of cyclic peptides and peptidomimetics. RAFT... 

The Hantzsch reaction has also been utilized in the combinatorial synthesis of cyclic peptidomimetics 13 (14ACSCS001), peptide macrocycles 14 (14ACSCS71),oxazole-thiazole bis-heterocyclic compounds (14ACSCS39) (structures not shown). 

BENZOTRIAZOLE IN THE SYNTHESIS OF CYCLIC PEPTIDES AND CYCLIC PEPTIDOMIMETICS... 

Peptide Vaccines Peptide vaccines are chemically synthesized and normally consist of 8-24 amino acids. In comparison with protein molecules, peptide vaccines are relatively small. They are also known as peptidomimetic vaccines, as they mimic the epitopes. Complex structures of cyclic components, branched chains, or other configurations can be built into the peptide chain. In this way, they possess conformations similar to the epitopes and can be recognized by immune cells. An in silico vaccine design approach has been used to find potential epitopes. A critical aspect of peptide vaccines is to produce 3D structures similar to the native epitopes of the pathogen. 

Recent examples of successful peptide-ligand based discoveries of drug-like peptidomimetics include the discovery of SST antagonists, or the discovery of non-peptidic antagonists of the recently deorphanized urotensin II receptor at Sanofi-Aventis. ° As illustrated in Fig. 3, Flohr etal. used 3D models of the NMR solution structure of cyclic peptide derivatives of Urotensin II as a template for virtual 3D pharmacophore searches which resulted into non-peptidic candidates for lead optimization. 

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