Inhibition of the 26S proteasome as a possible mechanism for toxicity of heavy metal species.
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]ClO4 (1), [Cd(II)(L(iodo))Cl]·H2O (2), [Hg(II)(L(iodo))2]·4DMSO (3), [Pb(II)(L(iodo))NO3] (4), and [Sn(IV)(L(iodo))Cl3] (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.
Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA.
Dajena
D
Tomco
Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48201, USA.
Sara
S
Schmitt
Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA.
Mary Jane
MJ
Heeg
Barbara Ann Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Oncology, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Pathology, School of Medicine, Wayne State University, Detroit, MI 48201, USA; Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI 48201, USA. Electronic address: doup@karmanos.org.
Q Ping
QP
Dou
Department of Chemistry, Wayne State University, 5101 Cass Ave., Detroit, MI 48202, USA. Electronic address: cnverani@chem.wayne.edu.
Cláudio N
CN
Verani
D002478:Cells, Cultured; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019216:Metals, Heavy / Q000633:toxicity*; D008958:Models, Molecular; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism
D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D019216:Metals, Heavy; D046988:Proteasome Endopeptidase Complex; C061553:ATP dependent 26S protease
Cadmium & lead; Cell apoptosis; Mercury complexes; Proteasome inhibition activity; Toxicity of coordination complexes