Pseudoprolines (Psi Pro) in drug design: Direct insertion of Psi Pro systems into cyclosporin C

The insertion of acetals that exhibit variable structural features into com plex peptides such as cyclosporin C (CsC) results in oxazolidine derivative s (pseudoprolines, Psi Pro) of tailored physico-chemical and biological pro perties. N,O-Acetalation of the 2-threonine hydroxyl group and the precedin g 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 sugge sted by analytical HPLC, NMR spectroscopy and by kinetic measurements on bi nding with their receptor protein cyclophilin A (CypA) that were not time-d ependent. IC50 values for calf-thymus CypA were obtained by kinetic evaluat ion of its cis --> trans isomerase activity. The choice of the pam-substitu ted aryl dimethyl acetals allows the inhibitory properties of the correspon ding derivatives to be modulated to either prodrugs or moderately strongly binding cyclosporin C derivatives.