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

大石 真也

doi:10.1002/chin.200437255

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タイトル別名

Structure-Activity Relationship Studies on Cyclic RGD Peptides Utilizing Novel Alkene Dipeptide Isosteres
タチカンアルケンガタジペプチドイソスターオリヨウシタカンジョウ RGD ペプチドノコウゾウカッセイソウカンケンキュウ
Structure—Activity Relationship Studies on Cyclic RGD Peptides Utilizing Novel Alkene Dipeptide Isosteres

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説明

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_Vβ₃ and α_IIbβ₃ 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.<br>

収録刊行物

薬学雑誌

薬学雑誌 124 (5), 269-277, 2004

公益社団法人日本薬学会

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