Peptides cyclic, synthesis

Fig. 5. A safety-catch linker strategy for cyclic peptide synthesis.

Scheme 3 Cyclic peptide synthesis via a photo-induced single electron transfer and biradical coupling...

An RCM approach in conjunction with microwave heating has found other applications in cyclic peptide synthesis. Novel A-chain dicarba analogs of human relaxin-3 (H3 relaxin, INSL7) have been prepared and found to have applications in the treatment of stress and obesity. Artificial a-helices that feature a dicarba... 

Tulla-Puche J, Barany G (2004) On-resin native chemical ligation for cyclic peptide synthesis. J Org Chem 69 4101 107... 

Figure 3 summarizes the steps involved in cyclic peptide synthesis and these are described in more detail in Subheadings 3.1 and 3.2 for Boc and Fmoc methods, respectively. Carry out all procedures at room temperature and in a well-ventilated fume hood unless otherwise specified. The amounts of reagents are given based on a 0.5 mmol scale synthesis, which typically yields >10 mg of final product after purification. These procedures have been used in our laboratory to synthesize several classes of disulfide-rich cyclic peptides, including SFTI-1 (14 amino acids, one disulfide bond), cyclic Vcl.l (22 amino acid, two disulfide bonds), kalata B1 (29 amino acids, three disulfide bonds), MCoTI-II (34 amino acids, three disulfide bonds), and cyclic chlorotoxin (43 amino acids, four disulfide bonds) (Fig. 4). The procedures are described for manual synthesis but are also applicable to automated SPPS.

Chemical synthesis of natural cyclic peptides 97CRV2243. 

Studies on the synthesis of vancomycin and related cyclic peptides 98PAC391. 

Cyclosporine A (CsA) is a water-insoluble cyclic peptide from a fungus composed of 11 amino acids. CsA binds to its cytosolic receptor cyclophilin. The CsA/cyclophilin complex reduces the activity of the protein phosphatase calcineurin. Inhibition of this enzyme activity interrupts antigen receptor-induced activation and translocation of the transcription factor NEAT to the nucleus which is essential for the induction of cytokine synthesis in T-lymphocytes. 

Further, Wasserman and coworkers developed a direct acylation of stabilized phosphonium ylides by carboxylic acids in presence of the EDCI/DMAP (way c). This last method allows the introduction of a-aminoacid structures into the resulting P-oxo phosphorus ylides [19-25],opening the way to the total synthesis of depsipeptide elastase inhibitors [22,24] or cyclic peptidic protease inhibitor EurystatinA [20]. 

Dutton reported on the synthesis of an e-caprolactam analog of an anthelmintic cyclic peptide. The a-hydroxy-e-caprolactam 44 was generated in an ex chiral pool synthesis staring from malic acid. The a-hydroxy carboxylic acid unit was protected as a dioxolanone in 43. The protective group served simultaneously as the reactive function during cyclization lactam 44 formation succeeded by ring opening of the dioxolanone 43 by the nucleophilic attack of the amino function, Eq. (8) [14]. 

Liu, R. Zhang, P. Gan, T. Cook, J. M. Regiospecific bromination of 3-methylindoles with NBS and its application to the concise synthesis of optically active unusual tryptophans present in marine cyclic peptides. J. Org. Chem. 1997, 62, 7447-7456. 

Mazaleyrat, J.-P. Reboud-Ravaux, M. Wakselman, M. Synthesis and enzymic hydrolysis of cyclic peptides containing an anthranilic acid residue. Int. J. Peptide Protein Res. 1987, 30, 622-633. 

Redox-sensitive resin 24 designed for solid-phase peptide synthesis (SPPS) [29] was prepared from commercially available 2,5-dimethylben-zoquinone in seven steps [30] and loaded to a support via a Wittig reaction. Release of the peptide occurs using two sequential mild conditions, reduction with NaBH4 followed by TBAF-catalyzed cyclic ether formation (Scheme 8) which provide orthogonality to acid sensitive reactions. 

Jensen KJ, Alsina J, Songster MF, Vagner J, Albericio F, Barany G. Backbone amide linker (BAL) strategy for solid-phase synthesis of C-terminal-modified and cyclic peptides. J Am Chem Soc 1998 120 5441— 5452. 

Recently, Tam et al. extended their orthogonal ligation concept, using the thermodynamically driven formation of a thiazolidine ring for the synthesis of dendritic compounds that carry cyclic peptides at the surface, which were designated multiple cyclic antigen peptides (McAPs) [18,19]. 

A different approach toward cyclic peptides has been presented by Leatherbarrow and coworkers, employing ring-dosing metathesis (RCM) on a solid support [50], The authors reported on the synthesis of conformationally strained cyclic peptides of the Bowman-Birk inhibitor type, which are naturally occurring serine protease... 

Novel highly functionalized dipeptide isosters were synthesized via diastereoselective alkyl-arylation protocol of a glucose-derived (R)-tert-butanesulfinylimine. One of these novel sugar amino acid derivatives, a D-Ala-Ser/Thr isostere, was applied in a peptide synthesis protocol to afford a cyclic tetramer (Fig. 53).69... 

M-L Valero, E.Giralt, D Andreu. Optimized Asp/Glu side chain anchoring in synthesis of head-to-tail cyclic peptides by Boc/OFm/benzyl chemistry on solid phase, in R Ramage, R Epton, eds. Peptides 1996. Proceedings of the 24th European Peptide Symposium, Mayflower, Kingswinford, 1998, pp 857-858. 

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