Gold(I) complexes with thiosemicarbazones: Cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity

Complexes [Au(H2Ac4DH)Cl]∙MeOH (1) [Au(H22Ac4Me)Cl]Cl (2) [Au(H22Ac4Ph)Cl]Cl∙2H2O (3) and [Au(H22Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone (H2Ac4DH), its N(4)-methyl (H2Ac4Me) and N(4)-phenyl (H2Ac4Ph) derivatives, as well as with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone (H2Bz4Ph). The compounds were cytotoxic to Jurkat (immortalized line of T lymphocyte), HL-60 (acute myeloid leukemia), MCF-7 (human breast adenocarcinoma) and HCT-116 (colorectal carcinoma) tumor cell lines. Jurkat and HL-60 cells were more sensitive than MCF-7 and HCT-116 cells. Upon coordinating to the gold(I) metal centers in complexes (2) and (4), the cytotoxic activity of the H2Ac4Me and H2Bz4Ph ligands increased against the HL-60 and Jurkat tumor cell lines. 2 was more active than auranofin against both leukemia cells. Most of the studied compounds were less toxic than auranofin to peripheral blood mononuclear cells (PBMC). All compounds induced DNA fragmentation in HL-60 and Jurkat cells indicating their pro-apoptotic potential. Complex (2) strongly inhibited the activity of thioredoxin reductase (TrxR), which suggests inhibition of TrxR to be part of its mechanism of action.

[Au(H2Ac4DH)Cl]∙MeOH (1) [Au(H22Ac4Me)Cl]Cl (2) [Au(H22Ac4Ph)Cl]Cl∙2H2O (3) and [Au(H22Bz4Ph)Cl]Cl (4) were obtained with 2-acetylpyridine thiosemicarbazone, its N(4)-methyl, N(4)-phenyl derivatives, and with N(4)-phenyl 2-benzoylpyridine thiosemicarbazone. The compounds were cytotoxic to human tumor cell lines. 2 inhibited thioredoxin reductase's activity suggesting inhibition to be part of its mechanism of action.Figure optionsDownload as PowerPoint slideHighlights
► Gold(I) complexes were obtained with pyridine-derived thiosemicarbazones.
► All compounds were cytotoxic to HL-60 and Jurkat leukemia cells.
► Complex (2) was more cytotoxic than auranofin against leukemia cells.
► 2 strongly inhibited thioredoxin reductase’s (TrxR) activity.
► Inhibition of TrxR is probably part of the mechanism of action of 2.