A Series of Tripodal Cysteine Derivatives as Water‐Soluble Chelators that are Highly Selective for Copper(I)

Abstract

A series of tripodal ligands derived from nitrilotriacetic acid and extended by three converging, metal-binding, cysteine chains was synthesised. Their ability to bind soft metal ions thanks to their three thiolate functions was investigated by means of complementary analytical and spectroscopic methods. Three ligands that differ by the nature of the carbonyl group next to the coordinating thiolate functions were studied: L(1) (ester), L(2) (amide) and L(3) (carboxylate). The negatively charged derivative L(3), which bears three carboxylate functions close to the metal binding site, gives polynuclear copper(I) complexes of low stability. In contrast, the ester and amide derivatives L(1) and L(2) are efficient Cu(I) chelators with very high affinities, close to that reported for the metal-sequestering metallothioneins (log K≈19). Interestingly, these two ligands form mononuclear copper complexes with a unique MS(3) coordination in water solution. An intramolecular hydrogen-bond network involving the amide functions in the upper cavity of the tripodal ligands stabilises these mononuclear complexes and was evidenced by the very low chemical-shift temperature coefficient of the secondary amide protons. Moreover, L(1) and L(2) display large selectivities for the targeted metal ion that is, Cu(I), with respect to bioavailable Zn(II). Therefore the two sulfur-based tripods L(1) and L(2) are of potential interest for intracellular copper detoxication in vivo, without altering the homeostasis of the essential metal ion Zn(II).

A Sulfur Tripod Glycoconjugate that Releases a High‐Affinity Copper Chelator in Hepatocytes

“…The [Cu I (bcs) 2 ] 3‐ complex is formed as shown in Equation (1) and is easily detected by its visible absorption band (483 nm, 13 300 M −1 cm −1 ) 9a. 10, 12b Thus, when bcs ligand is added to any Cu I L complex, as shown in Equation (1), the more intense is the band at 483 nm, the lower is the stability of the Cu I L complex. …”

Tuning the coordination properties of multi-histidine peptides by using a tripodal scaffold: solution chemical study and catechol oxidase mimicking

“…Only a few reports are available in the literature describing metal ion interactions with tripodal peptides, [17][18][19][20][21][22][23][24][25][26][27][28] most of them are related to sulphur-containing ligands. [17][18][19][20][21] A series of tricarboxylic acids have been used 22 …”

“…Several tripodal peptides with different platforms have been designed as receptors of either organic molecules 16 or metal ions. [17][18][19][20][21][22][23][24][25][26][27][28][29] These ligands have several advantages in addition to the pre-organized structure and enhanced chelate effect. Using different amino acids, it is relatively easy to fine-tune the metal ion binding ability.…”

Design of intrahepatocyte copper(I) chelators as drug candidates for Wilson's disease

“…This led us to design ligands with three cysteine residues promoting a MS 3 coordination geometry for Cu + . Three cysteines were attached with peptide bonds to nonbiological scaffolds, which act as platforms to orient all the thiolate binding arms in the same direction to coordinate metal ions . Nitrilotriacetic acid was chosen as a tripodal anchor.…”

“…Nitrilotriacetic acid was chosen as a tripodal anchor. L 2 is the amide derivative and is represented in Figure . These chelating pseudopeptides are water‐soluble agents that display promising properties for in vivo Cu detoxification.…”