Position of Geminal Substitution of γ Amino Acid Residues Modulates Their Ability to Form Isolated Non-Helical C_(12) β-turn Mimics

摘要

We have attempted the construction of isolated αγ non-helical C_(12) β-turn mimics in Boc-Val-~DPro-γ~(x,x)-Leu-NHMe (x,x = 2/2, 3/3, 4/4) peptides by the incorporation of differentially dimethyl substituted γ amino acid residues at the (i + 2) position of the turn. Solution conformation was probed in detail using NMR and CD spectroscopy. Irrespective of the solvent polarity, peptide containing γ~(2,2) amino acid residues failed to form the isolated tight β-turn mimetic while peptides containing γ~(3,3) and γ~(4,4) residues successfully adopted isolated non-helical C_(12) β-turn mimic structure. The conformations adopted in solution were corroborated with DFT calculations. Such difference in the stereochemical ability of these di-substituted y amino acid residues arose from the difference in position of the di-substitution along the backbone of the residue. Thus prudent choice of the position of di-substitution in ω amino acid residues might be used as a strong peptidomimetic handle to control the structural design and generate complex structures.