Structure-activity relationship studies on cyclic RGD peptides utilizing novel alkene dipeptide isosteres.
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-psi[(E)-CH=CMe]-Val-type isosteres were carried out in essentially identical fashion to the previously reported preparation of psi[(E)-CH=CH]-type congeners. Alternatively, D-Phe-psi[(E)-CMe=CX]-Val-type isosteres (X=H or Me) were synthesized via stereoselective alkylation of beta-(1,3-oxazolidin-2-on-5-yl)-alpha,beta-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-psi[(E)-CX=CX]-Val-) (X=H or Me). alpha(V)beta(3) and alpha(IIb)beta(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 (1)H-NMR data in DMSO gave insight into the effects of the valine N-methyl group as well as the D-phenylalanine carbonyl oxygen.
Oishi
Shinya
S
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan. soishi@pharm.kyoto-u.ac,jp
D000475:Alkenes / Q000138:chemical synthesis* / Q000737:chemistry; D002625:Chemistry, Organic; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors*; D055601:Organic Chemistry Phenomena; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000475:Alkenes; D004151:Dipeptides; D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic