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

Abstract

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(L I)Cl] ( 1), [Cu(L I)OAc] ( 2), and [Cu(HL I)(L I)]OAc ( 3), where HL I 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 [CuL I] + as the minimal pharmacophore needed for proteasomal chymotryspin-like activity inhibition and permits some initial inference of mechanistic information.