Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone: cytotoxicity and effect on the enzymatic activity of thioredoxin reductase and glutathione reductase

Gabrieli L Parrilha; Karina S O Ferraz; Josane A Lessa; Kely Navakoski de Oliveira; Bernardo L Rodrigues; Jonas P Ramos; Elaine M Souza-Fagundes; Ingo Ott; Heloisa Beraldo

doi:10.1016/j.ejmech.2014.07.055

Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone: cytotoxicity and effect on the enzymatic activity of thioredoxin reductase and glutathione reductase

Eur J Med Chem. 2014 Sep 12:84:537-44. doi: 10.1016/j.ejmech.2014.07.055. Epub 2014 Jul 17.

Authors

Gabrieli L Parrilha¹, Karina S O Ferraz¹, Josane A Lessa², Kely Navakoski de Oliveira³, Bernardo L Rodrigues¹, Jonas P Ramos⁴, Elaine M Souza-Fagundes⁴, Ingo Ott³, Heloisa Beraldo⁵

Affiliations

¹ Departamento de Química, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
² Departamento de Química Geral e Inorgânica, Instituto de Química, Universidade do Estado do Rio de Janeiro, 20550-013, Rio de Janeiro, RJ, Brazil.
³ Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig, Germany.
⁴ Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil.
⁵ Departamento de Química, Universidade Federal de Minas Gerais, 31270-901, Belo Horizonte, MG, Brazil. Electronic address: hberaldo@ufmg.br.

PMID: 25058344
DOI: 10.1016/j.ejmech.2014.07.055

Abstract

Metal complexes with 2-acetylpyridine-N(4)-orthochlorophenylthiosemicarbazone (H2Ac4oClPh) were assayed for their cytotoxicity against MCF-7 breast adenocarcinoma and HT-29 colon carcinoma cells. The thiosemicarbazone and most of the complexes were highly cytotoxic. H2Ac4oClPh and its gallium(III) and tin(IV) complexes did not show any inhibitory activity against thioredoxin reductase (TrxR) and glutathione reductase (GR). The palladium(II), platinum(II) and bismuth(III) complexes inhibited TrxR at micromolar concentrations but not GR. The antimony(III) and gold(III) complexes strongly inhibited TrxR at submicromolar doses with GR inhibition at higher concentrations. The selectivity of these complexes for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. TrxR inhibition is likely a contributing factor to the mode of action of the gold and antimony derivatives.

Keywords: Anticancer drugs; Glutathione reductase; Metal complexes; Thioredoxin reductase; Thiosemicarbazones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Survival / drug effects
Chlorocebus aethiops
Coordination Complexes / chemistry*
Dose-Response Relationship, Drug
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Glutathione Reductase / antagonists & inhibitors*
HT29 Cells
Humans
Liver / enzymology
MCF-7 Cells
Models, Molecular
Molecular Structure
Organometallic Compounds / chemical synthesis
Organometallic Compounds / chemistry
Organometallic Compounds / pharmacology*
Rats
Structure-Activity Relationship
Thioredoxin-Disulfide Reductase / antagonists & inhibitors*
Thioredoxin-Disulfide Reductase / metabolism
Thiosemicarbazones / chemistry*
Vero Cells

Substances

Coordination Complexes
Enzyme Inhibitors
Organometallic Compounds
Thiosemicarbazones
Glutathione Reductase
Thioredoxin-Disulfide Reductase