Application of tri- and tetrasubstituted alkene dipeptide mimetics to conformational studies of cyclic RGD peptides |
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Authors: | Shinya Oishi Kazuhide Miyamoto Mikio Yamamoto Hirokazu Tamamura Yoshihiro Kuroda Nobutaka Fujii |
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Institution: | a Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan b Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka 422-8526, Japan c Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama 222-0002, Japan |
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Abstract: | The first application of a combination of novel ψ(E)-CX CX]-type alkene dipeptide isosteres to conformation studies of cyclic bioactive peptides was carried out (X=H or Me). For exploration of bioactive conformations of Kessler's cyclic RGD peptides, cyclo(-Arg-Gly-Asp-d-Phe-Val-) 1 and cyclo(-Arg-Gly-Asp-d-Phe-N-MeVal-) 2, d-Phe-ψ(E)-CX CX]-l-Val-type dipeptide isosteres were utilized having di-, tri- and tetrasubstituted alkenes containing the γ-methylated isosteres that have been reported to be potential type II′ β-turn promoters. All of the (E)-alkene pseudopeptides 3-6 exhibited higher antagonistic potency against αvβ3 integrin than 1, although potencies were slightly lower than 2. Detailed structural analysis using 1H NMR spectroscopy revealed that representative type II′ β/γ backbone arrangements proposed for 1, were not observed in peptides 3-6. Rather on the basis of 1H NMR data, the conformations of peptides 3-6 were estimated to be more analogous to those of the N-methylated peptide 2. |
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Keywords: | (E)-Alkene dipeptide isostere Cyclic RGD peptide Integrin Structure-activity relationship study |
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