A Water‐Soluble Peptoid that Can Extract Cu2+ from Metallothionein via Selective Recognition

다국어 초록 (Multilingual Abstract)

Selective binding of Cu2+ in water medium by a synthetic chelator is a promising therapeutic approach towards the treatment of various diseases including cancer. Chelation of Cu2+ is well exercised, however water‐soluble synthetic chelators that can selectively bind Cu2+ from a pool of competing metal ions at very high excess and/or can extract Cu2+ from a protein are hardly reported. Herein we describe the design and synthesis of an acetylated peptoid—N‐substituted glycine trimer—that incorporates a picolyl group at the N‐terminal, a non‐coordinating but structurally directing bulky chiral phenylethyl group at the C‐terminus and a modified 2,2′‐bipyridine group (PCA‐Nspe), which selectively binds Cu2+ to form a water‐soluble complex. We further demonstrate that the selectivity of PCA‐Nspe to Cu2+ is thermodynamically driven, leading to specific binding of Cu2+ in an aqueous solution containing up to 60‐fold excess of other biologically relevant metal ions such as Zn2+, Co2+, Mn2+, Ca2+, Mg2+, K+ and Na+. Based on spectroscopic data and DFT calculations of PCA‐Nspe as well as of a control peptoid having an achiral benzyl group instead of the phenylethyl side chain, we could suggest that the chiral and bulkier phenylethyl group at the C‐terminus controls the preorganization of the two ligands, and this might play a role in the selectivity of PCA‐Nspe. Significantly, we show that PCA‐Nspe can extract Cu2+ from the natural copper binding protein metallothionein.
Thermodynamically driven selective recognition of Cu2+: We present a design strategy for the preparation of a water‐soluble peptoid chelator that selectively binds and extracts Cu2+ from a pool of competitive metal ions or complexes, and from the copper‐binding protein metallothionein in water.