Synthesis and characterization of constrained cyclosporin A derivatives containing a pseudo-proline group

The chemical synthesis, conformational analysis and receptor binding studies of novel constrained cyclosporin A (CsA) analogues are described. The selective insertion of pseudo-proline (ΨPro) systems featuring different 2-C-substituents at the oxazolidine ring exerts dramatic effects upon the backbone conformation as demonstrated by NMR analysis. It is shown that the insertion of a ΨMeMepro at position 5 (Thr5CsA) maintains binding to cyclophilin A as well as to calcineurin and shows a 5-6 cis amide bond with all remaining amide bonds trans. The elaborated synthetic routes for generating ΨPro containing Cs derivatives pave the way for extended structure–activity relationship studies aiming at the design of potential pharmacologically active compounds with a selective activity profile.