The addition of 2 phosphine-sulfide-stabilized (PSS) donor motifs integrated into hinged and rigid thiophene rings confers them the capacity to form stable copper complexes and could potentially act as chelators to treat copper toxicity in Wilson disease, according to a recently published study in Inorganic Chemistry.

Patients with Wilson disease often require life-long treatment with chelators such as penicillamine, trientine, and zinc acetate to remove or prevent copper accumulation in vital tissue and its clinical consequences. Furthermore, cooper selective ligands also have the potential as an antiangiogenic agent in several types of cancer, the researchers noted.

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Due to the high affinity of cuproteins, the design of ligands capable of forming stable bonds with cooper represents a challenge, they added. Therefore, the authors aimed to create a high-affinity copper chelator using PSS binding motifs.

“The electron-withdrawing nature of the strongly polarized PS-moiety stabilizes the phosphine donor against protonation and oxidation while maintaining a strong affinity toward Cu(I),” the study team wrote.

The 2 resulting ligands underwent extensive analysis through spectrophotometric titrations, electrochemical experimentation, and X-ray crystal structures, revealing that the ligands could form stable mononuclear copper complexes. UV–vis spectroscopy showed that the ligands were cooper-selective and had minimum binding to magnesium and iron.

To test the effectivity and selectivity in animal cells, the authors incubated mouse fibroblasts supplemented with copper chloride and added the 2 ligands. The ligands effectively removed cooper from the cells with no significant effect over manganese, iron, and zinc concentration.

Ratiometric two-photon excitation microscopy was used to determine whether the ligands could cross the plasmatic membrane, revealing that they entered the cell to perform its chelating function.

“As revealed by two-photon excitation microscopy with the Cu(I)-selective ratiometric probe crisp-17, the ligands are also cell-permeant and can competitively remove Cu(I), thus rendering both ligands a valuable addition for selectively manipulating copper levels within complex biological systems,” the authors concluded.


Yu J, Bacsa J, Fahrni CJ. Conformationally preorganized high-affinity ligands for copper biology with hinged and rigid thiophene backbones. Inorg Chem. Published online January 20, 2023. doi:10.1021/acs.inorgchem.2c03524