A structure-activity relationship study was performed on cyclic RGD peptides using a combination of multisubstituted alkene dipeptide isosteres. To clarify the effects on bioactivity of a valine
N-methyl group in the
cyclo(-Arg-Gly-Asp-
D-Phe-MeVal-) peptide developed by Kessler's group, novel
D-Phe-Val-type isosteres with methyl-substituting groups on the olefin were designed and synthesized. Syntheses of
D-Phe-ψ[(
E)-CH=CMe]-Val-type isosteres were carried out in essentially identical fashion to the previously reported preparation of ψ[(
E)-CH=CH]-type congeners. Alternatively,
D-Phe-ψ[(
E)-CMe=CX]-Val-type isosteres (X=H or Me) were synthesized
via stereoselective alkylation of β-(1,3-oxazolidin-2-on-5-yl)-α,β-enoates using organocopper reagents. The resulting four isosteres were utilized in either solution- or solid-phase peptide synthesis to afford the cyclic RGD peptidomimetics,
cyclo(-Arg-Gly-Asp-
D-Phe-ψ[(
E)-CX=CX]-Val-) (X=H or Me). α
Vβ
3 and α
IIbβ
3 integrin antagonistic activities of the peptidomimetics along with Kessler's peptides were comparatively evaluated. In addition, structural calculations of these compounds by simulated annealing/energy minimization using dihedral and distance restraints derived from
1H-NMR data in DMSO gave insight into the effects of the valine
N-methyl group as well as the
D-phenylalanine carbonyl oxygen.
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