Application of tri- and tetrasubstituted alkene dipeptide mimetics to conformational studies of cyclic RGD peptides

The first application of a combination of novel ψ[(E)-CXdouble bond; length as m-dashCX]-type alkene dipeptide isosteres to conformation studies of cyclic bioactive peptides was carried out (X=H or Me). For exploration of bioactive conformations of Kesslerʹs cyclic RGD peptides, cyclo(-Arg-Gly-Asp-d-Phe-Val-) and cyclo(-Arg-Gly-Asp-d-Phe-N-MeVal-) , d-Phe-ψ[(E)-CXdouble bond; length as m-dashCX]-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 exhibited higher antagonistic potency against αvβ3 integrin than , although potencies were slightly lower than . Detailed structural analysis using 1H NMR spectroscopy revealed that representative type II′ β/γ backbone arrangements proposed for , were not observed in peptides . Rather on the basis of 1H NMR data, the conformations of peptides were estimated to be more analogous to those of the N-methylated peptide .