Thiocyclosporins: Preparation, Solution and Crystal Structure, and Immunosuppressive Activity
1991; Wiley; Volume: 74; Issue: 8 Linguagem: Inglês
10.1002/hlca.19910740833
ISSN1522-2675
AutoresDieter Seebàch, Soo Y. Ko, Horst Kessler, Matthias Köck, Michael Reggelin, Peter Schmieder, Malcolm D. Walkinshaw, Johann J. Bölsterli, Dorian Bevec,
Tópico(s)Quinazolinone synthesis and applications
ResumoAbstract 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 CDCL 3 , two conformers A and B, in a ratio 58:42 are found for [ 1 ψ 2 , 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 Sar 3 and MeLeu 4 residues. [ 4 ψ 5 , CSNH; 7 ψ 8 , CS–NH]CsA exhibits a conformation very similar to crystalline CsA. However, the D‐Ala 8 N H , MeLeu 6 Co γ‐turn H‐bond is not present in this dithio analogue. Also different is the MeBmt 1 side‐chain conformation, the dithio conformation showing a strong MeBmt 1 O H , Sar 3 C O 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.
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