Chiral Sulfoxide-Induced Single Turn Peptide alpha-Helicity

Inducing alpha-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce alpha-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone alpha-helicity.Natural Science Foundation of China [21102007, 21372023]; Shenzhen Science and Technology Innovation Committee [SW201110018, SGLH20120928095602764]; Pfizer-Peking University platform; Shenzhen Peacock Program [KQTD201103]; MOST of China [2013CB911501]; SZSTI Program [KQCX20130627103353535, GGJS20130329180714793]SCI(E)ARTICLEmark.e.flanagan@pfizer.com; wuyd@pkusz.edu.cn; lizg@pkusz.edu.cn