Cyclic peptidomimetics synthesis

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. 

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

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

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]. 

Scheme 2.69. Synthesis of cyclic peptidomimetics via Ugi-4CR/ring-closing metathesis.

The formation of medium size rings (8-10-membered) presents challenges based on strain and entropy (Scheme Reitz utilized RCM by (2a) of diallyl glycine to give the eight-membered cyclic olefin in equation (45). Two steps convert it to a scaffold for peptidomimetic synthesis. 

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... 

In the following discussion a selection of optimized procedures is presented for the synthesis on solid support of homodetic monocyclic and bicyclic as well as mixed homodetic/ heterodetic bicyclic peptides that contain at least one lactam ring, whereas heterodetic cyclic peptides containing other than amide bonds or peptidomimetics are not discussed here because of their unlimited diversity. 

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. 

Polymyxin B, (Section 16.1.6) is a cyclic heptapeptide with a pendent tripeptide segment that has topical antibiotic properties. The solid-phase synthesis is carried out with appropriate side-chain protections. The linear heptapeptide is removed from the resin and cyclized to yield the polymyxin B,. The synthesis of the peptidomimetic (S)-6-methyloctanoic acid is also outlined.136 ... 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

The design and synthesis of antifungal analogs of the cyclic peptide rhodopeptin (36) (Fig. 15.16) illustrate a recent application of peptidomimetic scaffolding, where the structure of the biological target is not knovm. After structure-activity relationship (SAR) studies, the important side-chains of the peptide... 

Peterson LW, Sala-Rabanal M, Krylov IS, Serpi M, Kashemirov BA, McKenna CE (2010) Serine side chain-linked peptidomimetic conjugates of cyclic HPMPC and HPMPA synthesis and interaction with hPEPTl. Mol Pharm 7 2349-2361... 

Cyclic pentapeptide is a potent inhibitor of a4] l-mediated cell adhesion to CS-1 site and VCAM with IC50 ranging from 2 to 9 pM in cell adhesion assays. Under this background, Ho and Broka reported the synthesis of peptidomimetic tricyclic tetrahydrobenzo [ij] quinolone in 2000 [95]. Palladium-catalyzed alkoxycarb-onylation of aryl triflate was applied and produced the needed intermediate in moderate yield (Scheme 10.20). 

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