Cyclic α,α‐Disubstituted α‐Amino Acids with Menthone in Their Side‐Chains Linked through an Acetal Moiety and Helical Structures of Their Peptides

Abstract

The chiral cyclic α,α‐disubstituted α‐amino acids, Hms[(–)‐Men] and Hms[(+)‐Men] with (–)‐ and (+)‐menthones in their side‐chains, respectively, were designed and synthesized. Hms[(–)‐Men] homopeptides and Hms[(–)/(+)‐Men]‐containing l‐Leu‐based peptides were prepared in order to investigate the conformational properties of Hms[(–)/(+)‐Men]. The preferred conformations of the Hms[(–)/(+)‐Men]‐containing peptides were determined by FTIR, 1H NMR, and CD spectroscopy in solution, and by X‐ray crystallographic analysis in the crystal state. Conformational analysis in solution revealed similar right‐handed (P) 310‐helical structures for the Hms[(–)/(+)‐Men]‐containing octapeptides. In the solid state of the hexapeptides, the peptide main‐chain structures were mostly similar; however, some differences were observed in the side‐chains. The Hms[(–)/(+)‐Men] may function as helical inducers, but their side‐chain chiralities had only a negligible effect on their helical‐screw control of l‐Leu‐based peptides.

Enhanced and Prolonged Cell-Penetrating Abilities of Arginine-Rich Peptides by Introducing Cyclic α,α-Disubstituted α-Amino Acids with Stapling

“…A stapled peptide was provided by the incorporation of a staple into the side chain of the nonstapled peptide. Peptides containing cyclic dAAs prefer to form helical structures − and have been reported as helical functional peptides such as peptide catalysts − and antimicrobial peptides. , We expected the synergistic effects between the introduction of cyclic dAAs and the staple in Arg-rich peptides to improve their helicities in aqueous solution and cell-penetrating abilities for a long time.…”

Low pH-triggering changes in peptide secondary structures

“…Hexapeptides 6a/6b showed bands assigned to peptide NH groups intramolecularly hydrogen bonded to acetal oxygens, which is consistent with a previous study. 26,32 On the other hand, the Hms octapeptide 11 33 showed the typical CD spectrum of a random structure with a negative maximum at 195 nm and positive maximum at 215 nm (Fig. 2).…”

“…The acyclic dAA with a diol-side chain, Cbz-Hms-OMe 2, was synthesized via Cbz-Hms(Ipr)-OMe 1a (Scheme 1). Acetalization using cyclohexanone was achieved according to previously reported methods, 26 giving Cbz-Hms(c-Hex)-OMe 1b in a moderate yield. We then prepared octapeptides with Hms(Ipr), Hms(c-Hex), or Hms in the L-Leu sequences (Scheme 2), in order to evaluate the effects of side chain structures on peptide secondary structures and low pH sensitivity.…”