Conformational control of cyclosporin through substitution of the N-5 position. A new class of cyclosporin antagonists.
Cyclosporin A (CsA) can be regiospecifically alkylated at the NH of Val-5 with reactive bromides in the presence of phosphazene-base P4-t-Bu to yield derivatives 2-5. These are devoid of immunosuppressive activity in vitro but they have binding affinity for cyclophilin A (CypA) similar to that of CsA and thus represent a new class of cyclosporin antagonists. 1H NMR (DMSO-d6) studies have shown that the compounds exist in a single, all trans conformation. A comparison of this NMR data with X-ray crystallographic analysis of a CypA/CsA derivative complex demonstrates that the solution structure does not correspond to the bioactive conformation.
Papageorgiou
C
C
Sandoz Pharma Ltd, Basel, Switzerland.
Kallen
J
J
France
J
J
French
R
R
D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000737:chemistry*; D006860:Hydrogen Bonding; D009682:Magnetic Resonance Spectroscopy; D011487:Protein Conformation; D014633:Valine / Q000737:chemistry*
D016572:Cyclosporine; D014633:Valine