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

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 α vβ 3 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 .