Peptidomimetics macrocyclic

An 8000-member library of trisamino- and aminooxy-l,3,5-triazines has been prepared by use of highly effective, microwave-assisted nucleophilic substitution of polypropylene (PP) or cellulose membrane-bound monochlorotriazines. The key step relied on the microwave-promoted substitution of the chlorine atom in monochlorotriazines (Scheme 12.7) [35]. Whereas the conventional procedure required relatively harsh conditions such as 80 °C for 5 h or very long reaction times (4 days), all substitution reactions were found to proceed within 6 min, with both amines and solutions of cesium salts of phenols, and use of microwave irradiation in a domestic oven under atmospheric reaction conditions. The reactions were conducted by applying a SPOT-synthesis technique [36] on 18 x 26 cm cellulose membranes leading to a spatially addressed parallel assembly of the desired triazines after cleavage with TFA vapor. This concept was later also extended to other halogenated heterocycles, such as 2,4,6-trichloropyrimidine, 4,6-dichloro-5-nitropyrimidine, and 2,6,8-trichloro-7-methylpurine, and applied to the synthesis of macrocyclic peptidomimetics [37]. 

This macrocyclic peptidomimetic compound exhibits potent inhibitory activity against Escherichia coli deformylase as well as strong antibacterial activity against both Gram-positive and Gram-negative bacteria. 

Finally, by introducing the aryl halide into the isocyanide component, as in 96, various macrocyclic peptidomimetics containing a nonsymmetrical endo biaryl ether bridge have been synthesized [89-91]. Aryl nucleophilic substitution also takes place in this case under standard base-promoted conditions. The synthesis was also carried out on solid phase. Selected examples are shown in Fig. 19, but also a... 

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. 

The same approach was recently used for the synthesis of a cyclopeptoid as potential inhibitor of the Tat/TAR complex of the HfV-1 virus (Scheme 24) [94, 95]. Two Ugi reactions were used to prepare fragment b that was coupled to fragment a to afford linear precursor c. The macrocyclic peptidomimetic d was obtained after cyclization employing Ugi reaction of amino acid c with paraformaldehyde and t-butyl isocyanide. 

Low-molecular-weight antagonists are attractive due to their low cost and bioavailability. Available literature indicates that many laboratories are attempting to create immunomodulators of small synthetic molecules, peptidomimetics, bacterial cell-wall components, macrocycles, corticosteriods, and others [74]. 

A second example is that involving the use of a glucopyranoside nonpeptide template by Hirschmann and coworkers [41, 46] for systematic functionalization to create novel peptidomimetics for the somatostain (SRIF) and substance-P (NKj) receptors. As illustrated in Figure 10, the cyclic hexapeptide SRIF agonist provided a macrocyclic lead stmcture that was transformed to a glucopyranoside template designed to substitute for a postulated 3 turn about the Tyr-D-Trp-Lys-Thr substructure of the parent peptide ligand. The prototype... 

Previous reviews on peptidomimetics have addressed pseudopeptides (11), macrocyclic mimetics (13), natural product mimetics (14), cyclic protease inhibitors (15), mimetics for receptor ligands (16-22), and earlier general overviews (23-29). This review will focus on the design process itself. Novel peptidomimetics in which the structural relationship between parent peptide and the peptidomimetic has been established by biophysical methods are used to clarify the principles. Successful approaches are highlighted to illustrate how these concepts are currently used. 

A novel concept for the synthesis of macrocyclic peptidomimetics 262, which incorporate heteroaromatic units, was reported (Scheme 39). This method involves sequential SNAr reactions of orthogonally protected amino groups of peptides and other linear oligomers on halogenated heterocycles such as 2,4,6-trichloro[l,3,5]triazines. The scope of this novel solid-phase approach was evaluated systematically by means of the SPOT-synthesis methodology on planar cellulose membranes <2000JC0361>. 

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). 

Escuder and Luis prepared a series of peptidomimetic cyclophanes constructed from m-phenylene and two identical amino acid units bridged by di-aminopolymethylenes of variable length [75,76]. The macrocycles were prepared by condensation of activated N-carbobenzoxy-protected amino acids with Q ,[Pg.105]

Many protease/peptidase inhibitor peptidomimetics include a-ketoamide moieties as key bioactive functionalities and the Passerini reaction provides a facile entry for their preparation through the oxidation of a-hydroxy amides. Researchers at Schering-Plough have utilized this strategy to synthesize a variety of a macrocyclic a-ketoamides towards the development of Hepatitis C virus (HCV) NS3 protease inhibitors. Aldehyde 56 was treated with allylisocyanide and acetic acid to give a-acyloxyamide... 

Copper-catalyzed azide-alkyne cycloadditions have become increasingly popular due to their almost quantitative formation of 1,4-substituted triazoles, regioselectively, and the remarkable functional group tolerance, which is important when dealing with peptides or peptidomimetics. The majority of publications on dipolar cycloaddition reactions in peptide chemistry has focused on the CuAAC and reported peptide bond isosteres, side-chain functionalization, glycoconjugation, macrocyclization and isotopic labeling of peptides. We will most likely see an inaeasing number of applications where peptides are modified by dipolar cycloadditions in the future. 

Barrett AGM, Hennessy AJ, Vezouet RL, Procopiou PA, Searle PW, Stefaniak S, Upton RJ, White AJP, Williams DJ. Synthesis of diverse macrocyclic peptidomimetics utilizing ring-closing metathesis and solid-phase synthesis. J. Org. Chem. 2004 69 1028-1037. 

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