Synthesis, conformation and immunosuppressive activity of a conformationally restricted cyclosporin lactam analog

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Abstract
Cyclosporine A (CsA, 1), an immunosuppressive cyclic undecapeptide, in apolar solvents adopts a II'' .beta.-turn at the Sar3-MeLeu4 residues. [D-Proline3]Cs has been reported to be a nonimmunosuppressive analogue in which the II'' .beta.-turn is retained. In order to determine if this loss of activity is caused by steric hindrance between the Cs analogue and its receptor or is caused by a change in the peptide conformation, analogue that stabilizes a II'' .beta.-turn has been synthesized, [lactam3,4]Cs (3). The conformation have been established by 1D difference NOE and 2D (NOESY or ROESY) NMR. The conformations of [lactam3,4]Cs (4) and [D-MeAla3]Cs are indistinguishable from that of CsA in solution. [L-MeAla3]Cs (3) was found to adopt a conformation with a cis amide bond between Sar3 and MeLeu4. The inhibition of concanavalin A stimulated thymocytes by CsA (1), [D-MeAla3]Cs (2), [L-MeAla3]Cs (3), and [lactam3,4]Cs (4) were gave IC50 values (nM) of 5, 6, 100, and 100, respectively. The weak immunosuppressive activity of [lactam3,4]Cs (4) possessing the II'' .beta.-turn suggests that the loss of activity for 4 is due to steric hindrance with the Cs receptor.