Structure of cyclosporine and its metabolites: total synthesis of cyclosporine metabolites formed by oxidation at positions 4 and 9 of cyclosporine. Preparation of leucine-4-cyclosporine, (g-hydroxy)-N-methyl-leucine-9-cyclosporine and leucine-4-(g-hydroxy)-N-methyl-leucine-9-cyclosporine
Résumé
The syntheses of the cyclosporine metabolites Leu-4-cyclosporine (AM4N), (gamma-OH)MeLeu-9-cyclosporine (AM9) and Leu-4-(gamma-OH)MeLeu-cyclosporine (AM4N9) were completed. Aspartic acid was used as starting material to prepare peptides containing (gamma-OH)MeLeu residues. The structure of metabolite M13 was definitively established as being Leu-4-(gamma-OH)MeLeu-9-cyclosporine. The immunosuppressive activity in vitro of these synthesized metabolites was compared with that of cyclosporine and metabolite AM1.