Synthesis, biological activity, and conformational analysis of (2S,3R,4S)-MeBmt1-cyclosporin, a novel 1-position epimer of cyclosporin A.
Cyclosporin A (CsA, 1), an immunosuppressive cyclic undecapeptide, contains a unique amino acid, (4R)-4-[(E)-butenyl]-4,N-dimethyl-L-threonine (MeBmt), that appears to be critically involved in the biological activity of CsA. In order to further explore the effect that structural elements in MeBmt have on the conformation and biological activity of CsA, the 4-epimer of MeBmt [(4S)-MeBmt, 2] and the corresponding CsA analogue [(4S)-MeBmt1-CsA, 3] have been synthesized. Biological assay using concanavalin A stimulated thymocytes indicated that (4S)-MeBmt1-CsA (3) has only 2-4% immunosuppressive activity relative to CsA. The NMR analysis by 1D and 2D NMR methods establishes the conformation of 3, of which the 33-membered cyclic peptide ring system in chloroform is very similar to that of CsA. However, the NMR analysis also reveals that the 1-position side chain orientation in (4S)-MeBmt1-CsA (3) is very different from that of CsA. Specifically, the (4S)-MeBmt alpha,beta-torsion angle (chi 1) has been rotated approximately 120 degrees relative to that of CsA, and the orientation of the butenyl side chain relative to the 33-membered peptide backbond is different. The orientation of the (4S)-MeBmt side chain is consistent with the possible conformations calculated for (4S)-MeBmt1-CsA (3) by using molecular mechanics (in vacuo) calculations. The conformational analysis suggests that the loss of biological activity for 3 results from an altered conformation of the 1-position side chain relative to the peptide backbond due to the changed chirality at C4 of MeBmt.
School of Pharmacy, University of Wisconsin, Madison 53706.
D H
DH
Rich
C Q
CQ
Sun
D
D
Guillaume
B
B
Dunlap
D A
DA
Evans
A E
AE
Weber
D055598:Chemical Phenomena; D002621:Chemistry; D003208:Concanavalin A / Q000037:antagonists & inhibitors; D003524:Cyclosporins / Q000138:chemical synthesis* / Q000494:pharmacology; D007166:Immunosuppressive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D003524:Cyclosporins; D007166:Immunosuppressive Agents; D003208:Concanavalin A