Peptide-Based Pseudo[2]- and [3]rotaxanes Assembled via Square-Planar Palladium Coordination

Interlocked peptide molecules exhibit peptidase resistance as well as enzyme inhibitory activity, making them promising candidates for peptide-based drugs. Lasso peptides possess a [1]rotaxane structure, in which a peptide chain threads through the cavity of the cyclic peptide moiety. However, the construction of such peptide-based interlocked structures remains highly challenging, and the total chemical synthesis of natural lasso peptides has not yet been achieved. Here, we aim to develop a synthetic method for a peptide-based rotaxane using a metal-template strategy. A macrocyclic complex bearing a Pd(II) ion fixed by a pincer ligand is employed to examine the threading of Val-8mer in DMSO. Pseudorotaxane formation is assessed by characteristic ¹H NMR shifts and DOSY measurements, and is confirmed by electrospray ionization mass spectrometry (ESI-MS). Titration and variable-temperature (VT) NMR experiments are also performed to elucidate the dynamic behavior of the rotaxanation. These results demonstrate the feasibility of creating lasso-peptide-like architectures via metal-templated rotaxanation, providing a new strategy for the synthesis of natural and artificial lasso peptides.