Inhibition of the 26S proteasome as a possible mechanism for toxicity of heavy metal species.

Abstract In this paper we report on the synthesis of five metal complexes coordinated to the [NN′O] ligand HL iodo (2,4-diiodo-6-((pyridine-2-ylmethylamino)methyl)phenol), namely [Al III (L iodo ) 2 ]ClO 4 ( 1 ), [Cd II (L iodo )Cl]·H 2 O ( 2 ), [Hg II (L iodo ) 2 ]·4DMSO ( 3 ), [Pb II (L iodo )NO 3 ] ( 4 ), and [Sn IV (L iodo )Cl 3 ] ( 5 ). Species 1 – 5 are thoroughly characterized by spectroscopic and spectrometric methods, as well as by elemental analysis. X-ray crystallography results for complex 3 indicate the presence of Hg(II) ion hexacoordinated to two facially oriented [NN′O] ligands, whereas for complex 5 an Sn(IV) ion chelates to one deprotonated ligand and three chlorido coligands. The toxicity of species 1 – 5 is tested against transformed human prostate epithelial cells CRL2221 and we observe that the five complexes demonstrate high levels of cell growth inhibition in a dose-dependent manner. In order to evaluate the relationship between these species and the proteasome, we test 1 – 5 against purified 20S, CRL2221 cell extracts, and intact cells, followed by the measurement of the percent chymotrypsin-like activity inhibition levels. Results suggest a good correlation between the toxicity of [Hg II (L iodo ) 2 ]·4DMSO ( 3 ) and proteasome inhibition.