多置換アルケン型ジペプチドイソスターを利用した環状RGDペプチドの構造活性相関研究

概要

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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-(l,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 anb/?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 TV-methyl group as well as the D-phenylalanine carbonyl oxygen.
公益社団法人日本薬学会の論文
2004-05-01