Peptidomimetics cyclic

Cyclization is one of the earliest techniques applied to design peptidomimetics. Cyclic peptides are more stable to amide bond hydrolysis and allow less conformational flexibility consequently, the resulting analogs are anticipated to be more selective and less toxic. Methods for restricting conformations include peptide backbone cyclization, disulfide bond formation, side-chain cyclization, and metal ion chelation. 

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. 

The idea for macrocydic peptidomimetic inhibitors of PDF originated from the structure of the reverse hydroxamate BB-3497 that was reported by Clements et al. [73]. On this basis, Hu et al. [81] designed the cyclic compound 135, in which a nonyl group serves as the cross-linked Pi and P3 side chain, as depicted in Fig. 8. 

G. P. Camenisch, W. Wang, B. Wang, R. T. Borchardt, A Comparison of the Bioconversion Rates and the Caco-2 Cell Permeation Characteristics of Coumarin-Based Cyclic Prodrugs and Methylester-Based Linear Prodrugs of RGD Peptidomimetics , Pharm. Res. 1998, 15, 1174- 1181. 

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. 

Cyclic Peptidomimetics and Pseudopeptides from Multicomponent Reactions... 

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. 

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... 

Scheme 11 Synthesis of confonnationally restricted cyclopeptides and cyclic peptidomimetics by the Ugi4CR/RCM strategy...

Riva and coworkers obtained conformationally restricted cyclic peptidomimetics 13a and b by a tandem Ugi-4CR/RCM procedure as reported before (Scheme 13). The initial A-alkylated dipeptide moiety was formed in the Ugi reaction of A-Boc... 

Scheme 17 Synthesis of cyclic peptidomimetics by sequential Zhu-3CR/azide-alkyne dipolar cycloaddition strategy...

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