Synthesis of differentially protected N-acylated reduced pseudodipeptides as building units for backbone cyclic peptides.
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.
Besser
D
D
Institut für Biochemie und Biophysik, Friedrich-Schiller-Universität Jena, Germany.
Müller
B
B
Agricola
I
I
Reissmann
S
S
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*
D000596:Amino Acids; D002264:Carboxylic Acids; D004151:Dipeptides; D005449:Fluorenes; C016456:N(alpha)-fluorenylmethyloxycarbonylamino acids; D013004:Somatostatin