Metal complexes of 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone: cytotoxic activity and investigation on the mode of action of the gold(III) complex.
Complexes [Au(PyCT4BrPh)Cl]Cl (1), [Pt(PyCT4BrPh)Cl]0.5KCl (2), and [Pd(PyCT4BrPh)Cl]KCl (3) were obtained with 3-(4-bromophenyl)-1-pyridin-2-ylprop-2-en-1-one thiosemicarbazone (HPyCT4BrPh). Although complexes (2) and (3) did not exhibit potent cytotoxic activity, HPyCT4BrPh and its gold(III) complex (1) proved to be highly cytotoxic against HL-60 (human promyelocytic leukemia) and THP-1 (human monocytic leukemia) cells, and against MDA-MB 231 and MCF-7 (human breast adenocarcinoma) solid tumor cells. Except for HL-60 cells, upon coordination to gold(III) a 2- to 3-fold increase in the cytotoxic effect was observed. An investigation on the possible biological targets of the gold(III) complex was carried out. Complex (1) but not the free thiosemicarbazone inhibits the enzymatic activity of thioredoxin reductase (TrxR). The affinity of 1 for TrxR suggests metal binding to a selenol residue in the active site of the enzyme. While HPyCT4BrPh was inactive, 1 was able to inhibit topoisomerase IB (Topo IB) activity. Hence, inhibition of TrxR and Topo IB could contribute to the mechanism of cytotoxic action of complex (1).
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Luciana B P
LB
Sâmia
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Gabrieli L
GL
Parrilha
Departamento de Farmácia, Universidade Federal de Juiz de Fora (UFJF), Governador Valadares, MG, 35010-177, Brazil.
Jeferson G
JG
Da Silva
Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Jonas P
JP
Ramos
Departamento de Fisiologia e Biofísica, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil.
Elaine M
EM
Souza-Fagundes
Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.
Silvia
S
Castelli
Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.
Venn
V
Vutey
Department of Biology, University of Rome "Tor Vergata", Via della Ricerca Scientifica 1, 00133, Rome, Italy.
Alessandro
A
Desideri
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil. hberaldo@ufmg.br.
Heloisa
H
Beraldo
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013880:Thioredoxin-Disulfide Reductase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013882:Thiosemicarbazones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D011725:Pyridines; D013882:Thiosemicarbazones; D013880:Thioredoxin-Disulfide Reductase; D004264:DNA Topoisomerases, Type I; C528909:TOP1 protein, human
Chalcone; Cytotoxic activities; Metal complexes; Thioredoxin reductase; Thiosemicarbazone; Topoisomerase IB