Diastereoselective synthesis of new psi[(E)-CH=CMe]- and psi[(Z)-CH=CMe]-type alkene dipeptide isosteres by organocopper reagents and application to conformationally restricted cyclic RGD peptidomimetics.
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.
Oishi
Shinya
S
Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan.
Kamano
Takae
T
Niida
Ayumu
A
Odagaki
Yoshihiko
Y
Hamanaka
Nobuyuki
N
Yamamoto
Mikio
M
Ajito
Keiichi
K
Tamamura
Hirokazu
H
Otaka
Akira
A
Fujii
Nobutaka
N
D000475:Alkenes / Q000737:chemistry*; D002625:Chemistry, Organic / Q000379:methods; D003300:Copper; D003500:Cyclization; D004151:Dipeptides / Q000138:chemical synthesis*; D018716:Molecular Mimicry; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000737:chemistry*; D011392:Proline / Q000737:chemistry*; D013237:Stereoisomerism
D000475:Alkenes; D004151:Dipeptides; D009942:Organometallic Compounds; D003300:Copper; D011392:Proline