Diastereoselective Synthesis of New <i>ψ</i>[(<i>E</i>)-CHCMe]- and <i>ψ</i>[(<i>Z</i>)-CHCMe]-type Alkene Dipeptide Isosteres by Organocopper Reagents and Application to Conformationally Restricted Cyclic RGD Peptidomimetics

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  • Shinya Oishi
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Takae Kamano
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Ayumu Niida
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Yoshihiko Odagaki
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Nobuyuki Hamanaka
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Mikio Yamamoto
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Keiichi Ajito
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Hirokazu Tamamura
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Akira Otaka
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan
  • Nobutaka Fujii
    Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan, Minase Research Institute, Ono Pharmaceutical Co. Ltd., Mishima-gun, Osaka, 618-8585, Japan, and Pharmaceutical Research Center, Meiji Seika Kaisha, Ltd., Kohoku-ku, Yokohama, 222-0002, Japan

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Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres corresponding to dipeptides having one N-methylamino acid, and application to bioactive peptides, are described. In a key reaction introducing the chiral alpha-alkyl group of the isosteres, organocopper-mediated alkylation of syn-beta-methylated gamma-mesyloxy-alpha,beta-enoate 26a afforded E- and Z-isomers of anti-S(N)2' products in a solvent-dependent manner. The resulting two isosteres, D-Phe-psi[(E)-CH=CMe]-L-Val 27a and D-Phe-psi[(Z)-CH=CMe]-L-Val 28b, which corresponded to trans- and cis-conformers of D-Phe-L-MeVal, respectively, were utilized in a structure-activity relationship study on cyclic RGD peptides 1 and 2, in company with a psi[(E)-CH=CH]-type alkene dipeptide isostere, D-Phe-psi[(E)-CH=CH]-L-Val. The cyclic isostere-containing pseudopeptides 3, 4, and 40 were synthesized and biological activity against integrin alpha(V)beta(3) and alpha(IIb)beta(3) receptors were also evaluated.

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