Abstract

The insertion of acetals that exhibit variable structural features into complex peptides such as cyclosporin C (CsC) results in oxazolidine derivatives (pseudoprolines, Psi Pro) of tailored physico-chemical and biological properties. N,O-Acetalation of the 2-threonine hydroxyl group and the preceding amide nitrogen of CsC is achieved by treating the molecule with a number of both arylated and non-arylated dimethyl acetals. The Psi Pro-containing CsC derivatives exhibit enhanced conformational backbone rigidity, as suggested by analytical HPLC, NMR spectroscopy and by kinetic measurements on binding with their receptor protein cyclophilin A (CypA) that were not time-dependent. IC50 values for calf-thymus CypA were obtained by kinetic evaluation of its cis --> trans isomerase activity. The choice of the pam-substituted aryl dimethyl acetals allows the inhibitory properties of the corresponding derivatives to be modulated to either prodrugs or moderately strongly binding cyclosporin C derivatives.

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