title: Synthesis of differentially protected N-acylated reduced pseudodipeptides as building units for backbone cyclic peptides.
abstract: Backbone cyclization has become an important method for generating or stabilizing the bioactive conformation of peptides without affecting the amino acid side-chains. Up to now, backbone cyclic peptides were mostly synthesized with bridges between N-amino- and N-carboxy-functionalized peptide bonds. To study the influence of a more flexible backbone on the biological activity, we have developed a new type of backbone cyclization which is achieved via the N-functionalized moieties of acylated reduced peptide bonds. As described in our previous publications, the formation of N-functionalized dipeptide units facilitates the peptide assembly compared with the incorporation of N-alkyl amino acids. Besides the racemization-free synthesis of Fmoc-protected pseudodipeptide esters with reduced peptide bonds, the new type of backbone modification allows the use of a great variety of omega-amino- and alpha,omega-dicarboxylic acids differing in chain length and chemical properties. Best results for the coupling of the omega-amino- and alpha,omega-dicarboxylic acids to the reduced peptide bond were obtained by the formation of mixed anhydrides with alkyl chloroformates. Whereas the protecting group combination of Z/OBzl in the dipeptide unit and Boc/OtBu for the N-functionalized moiety leads to the formation of 2-ketopiperazine during hydrogenation, the combination of Fmoc/OtBu and Alloc/OAll is very suitable for the synthesis of backbone cyclic peptides on solid support.
authors.affiliation: Institut für Biochemie und Biophysik, Friedrich-Schiller-Universität Jena, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Besser
authors.forename: B
authors.initials: B
authors.lastname: Müller
authors.forename: I
authors.initials: I
authors.lastname: Agricola
authors.forename: S
authors.initials: S
authors.lastname: Reissmann
mesh_terms: D000215:Acylation; D000596:Amino Acids / Q000138:chemical synthesis*; D002264:Carboxylic Acids / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004151:Dipeptides / Q000138:chemical synthesis*; D005449:Fluorenes / Q000138:chemical synthesis*; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D010452:Peptide Biosynthesis; D013004:Somatostatin / Q000737:chemistry*
chemical_list: D000596:Amino Acids; D002264:Carboxylic Acids; D004151:Dipeptides; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D013004:Somatostatin