Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity

Dieter Seebach, Soo Y. Ko, Horst Kessler, Matthias Köck, Michael Reggelin, Peter Schmieder, Malcolm D. Walkinshaw, J. Jakob Bölsterli, Dorian Bevec

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101 Scopus citations

Abstract

The reaction of cyclosporin A (CsA) with Lawesson's reagent under different conditions yields various thiocyclosporins, in which carbonyl O‐atoms and/or the hydroxy O‐atom of the MeBmt residue are replaced by an S‐atom. The position of the S‐atom is determined by NMR spectroscopy, and the conformations of the products are studied by NMR spectroscopy and X‐ray crystallography. Some of the thiocyclosporins show interesting conformational properties. Whereas one conformation strongly dominates for CsA in CDCL3, two conformers A and B, in a ratio 58:42 are found for [1ψ2, CS–NH]CsA. Extensive NMR studies including new 2D and 3D heteronuclear techniques and restrained MD calculations using ROE effects demonstrate that the major conformer A is identical to CsA, while the minor conformer B contains an additional cis peptide bond between the Sar3 and MeLeu4 residues. [4ψ5, CSNH; 7ψ8, CS–NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D‐Ala8NH, MeLeu6Co γ‐turn H‐bond is not present in this dithio analogue. Also different is the MeBmt1side‐chain conformation, the dithio conformation showing a strong MeBmt1OH, Sar3CO H‐bond. Immunosuppressive activities of thiocyclosporins are measured in IL‐2 and IL‐8 reporter gene assays. Their activities are discussed in relation to their conformations.

Original languageEnglish
Pages (from-to)1953-1990
Number of pages38
JournalHelvetica Chimica Acta
Volume74
Issue number8
DOIs
StatePublished - 11 Dec 1991

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