Serine-based cyclodepsipeptides on an adamantane building block: design, synthesis, and characterization of a novel family of macrocyclic membrane ion-transporting depsipeptides

Abstract

A simple two-step synthetic strategy provides a straightforward entry to a large variety of adamantane-containing serine-based cyclodepsipeptides. The design is flexible with respect to the choice of an amino acid, the ring size, and the nature of the template as illustrated here with the preparation of a large variety of serine-based macrocycles, for example, 18-membered simple cyclo(Adm-Ser-)₂ (4), 21-membered, S-S bridged, cyclo(Adm-Ser-Cyst-Ser-) (10), 24-membered cyclo(Adm-Ser-Val-)₂ (5a), cyclo(Adm-Ser-Leu-)₂ (5b), cyclo(Adm-Ser (Leu)-Val)₂ (6), pyridine-containing cyclo(Adm-Ser-Val-Py-Val-Ser-) (13), 26-membered cyclo(Adm-Ser-Ser-)₂ (8) and crown ether hybrid cyclo(Adm-Ser-TEG-Ser-) (12), and 36-membered cyclo(Adm-Ser-)₄ (7) and provides built-in handles (in the form of protected NH₂ and COOH groups) for attachment of suitable pendants leading to attractive models that may have multiple uses as membrane ionophores, scaffolds, or templates in the design of artificial proteins and for studying the structure-function relationship in biological receptors. This novel class of macrocyclic peptides are demonstrated to adopt β-turn type conformation and possess high efficiency in transporting Na⁺, Ca²⁺, and Mg²⁺ ions across model membranes. Amongst the cyclodepsipeptides reported here, the 24-membered macrocycle 6, containing two leucine residues symmetrically placed on the exterior of the ring, was found to be the most efficient ion-transporter in lipid bilayer membranes. Interestingly, no appreciable ion-transport was noticed by 18-membered cyclodepsipeptide (4) and by macrocycles 10, 12, and 13 possessing only one adamantane unit in their cyclic framework. These results show that a minimum of two adamantane units in a 24-membered ring size appears to be the optimum requirement for efficient membrane ion transport.