Tetrazole analogues of cyclolinopeptide A: Synthesis, conformation, and biology

Linear and cyclic analogs of cyclolinopeptide A (CLA) with two dipeptide segments (Val5-Pro6 and Pro6-Pro7) replaced by their tetrazole derivs. 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(Leu1-Ile2-Ile3-Leu4- Val5-Pro6-y[CN4]-Ala7 -Phe8-Phe9) were investigated by NMR and computational techniques. The overall soln. structure of this cyclic peptide resembles that obsd. for the CLA in the solid state. These studies of cyclic tetrazole CLA analog confirm that the 1,5-disubstituted tetrazole ring functions as an effective, well-tolerated cis-amide bond mimic in soln. The peptides were examd. for their immunosuppressive activity in the humoral response test. For cyclic analogs the immunosuppressive activity, at low doses, is equal in magnitude to the activity presented by cyclosporin A and native CLA. The conformational and biol. data seem indicate that the Pro-Pro-Phe-Phe moiety and the preservation of the CLA backbone conformation are important for immunosuppressive activity.