Metals in anticancer therapy: Copper(II) complexes as inhibitors of the 20S proteasome

Selective 20S proteasomal inhibition and apoptosis induction were observed when several lines of cancer cells were treated with a series of copper complexes described as [Cu(LI)Cl] (1), [Cu(LI)OAc] (2), and [Cu(HLI)(LI)]OAc (3), where HLI is the ligand 2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol. These complexes were synthesized, characterized by means of ESI spectrometry, infrared, UV–visible and EPR spectroscopies, and X-ray diffraction when possible. After full characterization species 1–3 were evaluated for their ability to function as proteasome inhibitors and apoptosis inducers in C4-2B and PC-3 human prostate cancer cells and MCF-10A normal cells. With distinct stoichiometries and protonation states, this series suggests the assignment of species [CuLI]+ as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.

Graphical abstractThree well characterized discrete copper complexes with asymmetric phenol-substituted ligands are able to inhibit the proteolytic activity of the 20S proteasome. Evidence for a minimal pharmacophore suggests a potential basis for new cancer therapies with tunable and cost-effective metallodrugs.Figure optionsDownload full-size imageDownload as PowerPoint slide