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

R. M. Wenger (1) , K. Martin (1) , C. Timbers (1) , Anne Tromelin (1, 2)

1 Sandoz Pharma Ltd.
2 INRA - Institut National de la Recherche Agronomique

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.

Mots clés: metabolites; peptidic synthesis; immunosuppressive activity; human-liver; analogs; cyclophilin; 1-position; requirements; chemistry; cyclosporin; analog; peptide synthesis; recognition of species; liver function tests

Mots clés: cyclosporine; métabolite; analogue; cyclophiline; synthèse peptidique; identification; foie; conformation; disposition

Domaines: Chimie organique; Chimie thérapeutique

R. M. Wenger, K. Martin, C. Timbers, Anne Tromelin. 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. CHIMIA, 1992, 46 (7-8), pp.314-322. ⟨hal-01812826⟩