Thiocyclosporins: preparation, solution and crystal structure, and immunosuppressive activity
D. Seebach, S.Y. Ko, H. Kessler, M. Koeck, M. Reggelin, P. Schmieder, M.D. Walkinshaw, J.J. Boelsterli, D. Bevec
Helv. Chim. Acta (1991) 74, 1953-1990
The reaction of cyclosporin A (I) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl atoms and/or the hydroxy O atom of the 3-hydroxy-N,4-dimethyl-L-2-amino-6-octenoyl (MeBmt) residue are replaced by an S atom. The position of the S atom is determined by NMR, and the conformations of the products are studied by NMR and x-ray crystallographie. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for I in CDCl3, two conformers, in a ratio 58:42 are found for [1y2,CSNH]-I. Extensive NMR studies including new 2- and 3-dimensional heteronuclear techniques and restrained molecular dynamics calculations using ROE effects demonstrate that the major conformer is identical to I, while the minor conformer contains an additionanl cis peptide bond between the Sar3 and MeLeu4 residues. [4y5,CS-NH,7y8,CS-NH]-I exhibits a conformation very similar to crystaline I. However, the D-Ala8 NH, MeLeu6 CO g-turn H-bond is not present in this dithio analog. Also different is the MeBmt1 side-chain conformation, the dithio conformation showing a strong MeBmt1 OH, Sar3 CO H-bond. Immunosuppressive activities of thiocyclosporins are measured in interleukin-2 and -8 reporter gene assays. Their activities are discussed in relation to their conformations.