SYNTHESIS AND BIOLOGICAL PROPERTIES ANALOGUES OF C YCLOLINOPEPTIDE A CONTAINING HOMOPHENYLALANINE OR α-HYDROXYMETHYLPHENYLALANINE

摘要

The search of new immunosupressants, exhibiting the mechanism of action characteristic for cyclosporine A (CsA) and FK-506 is an important challenge for medicinal chemistry. Cyclolinopeptide A (CLA) natural cyclic nonapeptide fcyclo(Leu-Ile-Ile-Leu-Val-Pro-Pro-Phe-Phe)] possesses a strong immunosuppressive activity comparable with that of CsA in low doses. The possibility of practical application of CLA as a therapeutic agent is limited due to its high hydrophobicity. It has been suggested that the tetrapeptide sequence Pro~6-Pro~7-Phe~8-Phe~9 is responsible for the interaction of the CLA molecule with the proper cellular receptor. In order to evaluate the role of this tetrapeptide unit for biological activity of native peptide, we decided to modified this fragment. We present linear and cyclic CLA analogues in which phenylalanine residues have been replaced with homophenylalanine (HoPhe) or amphiphilic α-hydroxmethylphenylalnine (HmPhe).