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, (γ-Hydroxy)-N-methyl-leucine-9-cyclosporine and Leucine-4-(γ-hydroxy)-N-methyl-leucine-9-cyclosporine

Abstract

The syntheses of the cyclosporine metabolites Leu-4-cyclosporine (AM4N), (γ-OH)MeLeu-9-cyclosporine (AM9) and Leu-4-(γ-OH)MeLeu-cyclosporine (AM4N9) were completed. Aspartic acid was used as starting material to prepare peptides containing (γ-OH)MeLeu residues. The structure of metabolite M13 was definitively established as being Leu-4-(γ-OH)MeLeu-9-cyclosporine. The immunosuppressive activity in vitro of these synthesized metabolites was compared with that of cyclosporine and metabolite AM1.