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Tetrazole analogues of cyclolinopeptide A: Synthesis, conformation, and biology
Author(s) -
Kaczmarek Krzysztof,
Jankowski Stefan,
Siemion Ignacy Z.,
Wieczorek Zbigniew,
Benedetti Ettore,
Di Lello Paola,
Isernia Carla,
Saviano Michele,
Zabrocki Janusz
Publication year - 2002
Publication title -
biopolymers
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.556
H-Index - 125
eISSN - 1097-0282
pISSN - 0006-3525
DOI - 10.1002/bip.10078
Subject(s) - tetrazole , chemistry , dipeptide , moiety , stereochemistry , peptide bond , amide , cyclic peptide , reagent , biological activity , peptide , tetrafluoroborate , ring (chemistry) , organic chemistry , biochemistry , in vitro , ionic liquid , catalysis
Linear and cyclic analogues of cyclolinopeptide A (CLA) with two dipeptide segments (Val 5 Pro 6 and Pro 6 Pro 7 ) replaced by their tetrazole derivatives were synthesized by the SPPS technique and cyclized using TBTU (O‐(benzotriazol‐1‐yl)‐1,1,3,3‐tetramethyluronium tetrafluoroborate) reagent. The conformational properties of the c(Leu 1 Ile 2 Ile 3 Leu 4 Val 5 Pro 6 ψ[CN 4 ]Ala 7 Phe 8 Phe 9 ) were investigated by NMR and computational techniques. The overall solution structure of this cyclic peptide resembles that observed for the CLA in the solid state. These studies of cyclic tetrazole CLA analogue confirm that the 1,5‐disubstituted tetrazole ring functions as an effective, well‐tolerated cis‐amide bond mimic in solution. The peptides were examined for their immunosuppressive activity in the humoral response test. For cyclic analogues the immunosuppressive activity, at low doses, is equal in magnitude to the activity presented by cyclosporin A and native CLA. The conformational and biological data seem indicate that the ProProPhePhe moiety and the preservation of the CLA backbone conformation are important for immunosuppressive activity. © 2002 Wiley Periodicals, Inc. Biopolymers 63: 343–357, 2002