Pseudoprolines (psiPro) in drug design: direct insertion of psiPro systems into cyclosporin C.
The insertion of acetals that exhibit variable structural features into complex peptides such as cyclosporin C (CsC) results in oxazolidine derivatives (pseudoprolines, psiPro) 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 psiPro-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 para-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.
Keller
M
M
Institute of Organic Chemistry, University of Lausanne BCH-Dorigny, Switzerland.
Wöhr
T
T
Dumy
P
P
Patiny
L
L
Mutter
M
M
D000818:Animals; D002417:Cattle; D021984:Cyclophilin A / Q000037:antagonists & inhibitors*; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000737:chemistry*; D015195:Drug Design; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000737:chemistry; D007202:Indicators and Reagents; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D011392:Proline / Q000031:analogs & derivatives*; D013950:Thymus Gland / Q000201:enzymology
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D007202:Indicators and Reagents; C100000:cyclosporin C; D011392:Proline; D021984:Cyclophilin A