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((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.Three 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.

Bis(2‐methylbenzimidazolyl)amine‐Derived Copper Complexes and Their Antineoplastic Activity

“…Initial hypotheses considered analogies with Pt to propose DNA binding, intercalation, and cleavage activity; proteasome inhibition has been postulated as a possible apoptotic mechanism. [6] Alternatively, evidence for oxidative damage by production of reactive oxygen species (ROS) has also been reported, and a form of nonapoptotic programmed cell death has also been observed. [7] More recently, caspase inhibition leading to paraptotic cell death has also been proposed as a cytotoxic route.…”

Structural characterization, ROS-inductive and proteasome inhibitory properties of ternary and binary copper(II) complexes of N2- and N2O2-ligands

“…b5 [Chymotrypsin-like (CT-L)], b2 [Trypsin-like (T-L)] and b1 [Caspase-like (C-L)]. Although numerous copper(II) complexes are known to inhibit proteasome, their ''proteasome inhibition profile", in terms of these three proteolytic sites, have not been investigated, as far as we know [69,18]. As part of our programme of characterizing the proteasome inhibition profile of copper(II) and other metal complexes, we herein report the inhibition of the three proteolytic sites of 20S mouse proteasome by the selected series of copper(II) complexes and CuCl 2 .…”

“…The 20S proteasome has three proteolytic sites, with chymotrypsin-like, trypsin-like and caspase-like activities respectively, capable of degrading different types of peptides or proteins. In comparison to normal cells, cancer cells have been reported to be more sensitive to proteasome inhibition, and the inhibition of chymotrypsinlike activity of the 20S proteasome in cancer cells by copper(II) complexes has resulted in apoptosis of the cells [12][13][14]. Unlike anticancer drugs like bortezomib, copper(II) complexes are likely to bind to the proteolytic sites by non-covalent interactions without modifying the nucleophilic Thr1 residue [15][16][17].…”

“…Copper (II) complex of 2,4-diiodido-6-((pyridine-2-yl-methylamino) methyl)phenol was a potent inhibitor of proteasome activity of live liver cancer cells but its precursors, viz. copper(II) chloride and its free ligand, showed insignificant inhibition [12]. Indole-3-acetic acid and indole-3-propionic acid could not inhibit 20S proteasome but their copper(II) complexes could inhibit 20S and 26S proteasomes [18].…”

“…One new biological property, which attracts anticancer drug researchers, is inhibition of proteasome which is a new validated target of anticancer compounds [9][10][11][12]. The human 26S proteasome is an ubiquitous, multi-catalytic protease which consists of 19S regulatory particles and a 20S proteolytic core [9].…”