Design, synthesis, conformational and membrane ion transport studies of proline-adamantane hybrid cyclic depsipeptides

Abstract

The design, synthesis, conformational, crystallographic, and ion transport studies of 30-membered, proline containing depsipeptides that incorporate the rigid low molecular weight lipophilic adamantane (Adm) building blocks are reported. The adamantyl groups provide the desired membrane permeability and conformational constraint for efficient transport in lipid membranes. The novel cyclic depsipeptides are: c[-Adm-C(O)-Pro-O-CH₂-CHR-NH-C(O)-Pro-C(O) Adm-C(O)-Pro-C(O)-NH-CHR-CH₂-O-Pro-C(O)] where R-H for A and R-CONH-Adm for B. Crystal structure analysis of A established that the two peptide segments are identical in formula and in conformation and that the peptides are bonded to the interleaving Adm at the 1 and 3 positions. However, the complete ring is highly asymmetric in shape since bonds for both Peptide-Adm-Peptide segments have the syn-anti motif. Torsional angles for the connecting bonds to Adm are -162°, +71° and -169°, -48°. The irregular clamshell shape of the molecule has three internal CO moieties directed in a manner that could provide three Na⁺O ligands. While A exhibited negligible transport of Na+ ions across membranes, peptide B endowed with two additional adamantanes in the periphery did transport Na+ ions from outside to inside.