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

Selective binding of Cu 2+ in water medium by a synthetic chelator is a promising therapeutic approach towards the treatment of various diseases including cancer. Chelation of Cu 2+ is well exercised, however water-soluble synthetic chelators that can selectively bind Cu 2+ from a pool of competing metal ions at very high excess and/or can extract Cu 2+ 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 Cu 2+ to form a water-soluble complex. We further demonstrate that the selectivity of PCA-Nspe to Cu 2+ is thermodynamically driven, leading to specific binding of Cu 2+ in an aqueous solution containing up to 60 folds excess of other biologically relevant metal ions such as Zn 2+ , Co 2+ , Mn 2+ , Ca 2+ , Mg 2+ , 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 Cu 2+ from the natural copper binding protein metallothionein.