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

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.

N(4)-tolyl-2-acetylpyridine thiosemicarbazones and their platinum(II,IV) and gold(III) complexes: cytotoxicity against human glioma cells and studies on the mode of action.

Complexes [Au(2Ac4oT)Cl][AuCl2] (1), [Au(Hpy2Ac4mT)Cl2]Cl·H2O (2), [Au(Hpy2Ac4pT)Cl2]Cl (3), [Pt(H2Ac4oT)Cl]Cl (4), [Pt(2Ac4mT)Cl]·H2O (5), [Pt(2Ac4pT)Cl] (6) and [Pt(L)Cl2OH], L = 2Ac4mT (7), 2Ac4oT (8), 2Ac4pT (9) were prepared with N(4)-ortho- (H2Ac4oT), N(4)-meta- (H2Ac4mT) and N(4)-para- (H2Ac4pT) tolyl-2-acetylpyridine thiosemicarbazone. The cytotoxic activities of all compounds were assayed against U-87 and T-98 human malignant glioma cell lines. Upon coordination cytotoxicity improved in 2, 5 and 8. In general, the gold(III) complexes were more cytotoxic than those with platinum(II,IV). Several of these compounds proved to be more active than cisplatin and auranofin used as controls. The gold(III) complexes probably act by inhibiting the activity of thioredoxin reductase enzyme whereas the mode of action of the platinum(II,IV) complexes involves binding to DNA. Cells treated with the studied compounds presented morphological changes such as cell shrinkage and blebs formation, which indicate cell death by apoptosis induction.

Spectroscopic and electrochemical characterization of gold(I) and gold(III) complexes with glyoxaldehyde bis(thiosemicarbazones): cytotoxicity against human tumor cell lines and inhibition of thioredoxin reductase activity.

Complexes [Au(2)(H(2)Gy3DH)(2)]Cl(2) (1), [Au(H(2)Gy3Me)]Cl(3) (2) and [Au(H(2)Gy3Et)]Cl(3) (3) were obtained with glyoxaldehyde bis(thiosemicarbazone) (H(2)Gy3DH) and its N(3)-methyl (H(2)Gy3Me) and N(3)-ethyl (H(2)Gy3Et) derivatives. The bis(thiosemicarbazones) and their gold(I) and gold(III) complexes exhibited anti-proliferative activity against HL-60, Jurkat (leukemia) and MCF-7 (breast cancer) cells at 10 µmol L(-1). Complex (2) was able to in vitro inhibit thioredoxin reductase (TrxR) activity, which suggests that inhibition of TrxR could be part of its mechanism of action.

Investigation on the pharmacological profile of 2,6-diacetylpyridine bis(benzoylhydrazone) derivatives and their antimony(III) and bismuth(III) complexes.

Complexes [Sb(HAcPh)Cl(2)] (1), [Sb(HAcpClPh)Cl(2)] (2), [Sb(HAcpNO(2)Ph)Cl(2)] (3) and [Bi(HAcPh)Cl(2)] (4), [Bi(HAcpClPh)Cl(2)] (5), [Bi(HAcpNO(2)Ph)Cl(2)] (6) were obtained with 2,6-diacetylpyridine bis(benzoylhydrazone) (H(2)AcPh), 2,6-diacetylpyridine bis(para-chlorobenzoylhydrazone) (H(2)AcpClPh), and 2,6-diacetylpyridine bis(para-nitrobenzoylhydrazone) (H(2)AcpNO(2)Ph). The bis(benzoylhydrazones) were inactive as antimicrobial agents against gram-positive and gram-negative bacteria and against Candida albicans but upon coordination to antimony(III) and bismuth(III) antimicrobial activity was demonstrated. The studied compounds were tested for their cytotoxic activities against Jurkat and HL60 (leukemia), MCF-7 (breast tumor), HCT-116 (colorectal carcinoma) and peripheral blood mononuclear (PBMC) cells. All bis(benzoylhydrazones) proved to be poorly cytotoxic. Upon coordination of the bis(benzoylhydrazones) to antimony(III) and bismuth(III) cytotoxicity significantly improved. Complex (5) presented high therapeutic indexes (TI = 11-508) against all cell lineages.

2-Benzoylpyridine-N(4)-tolyl thiosemicarbazones and their palladium(II) complexes: cytotoxicity against leukemia cells.

The palladium(II) complexes [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] were prepared with N(4)-ortho- (H2Bz4oT) N(4)-meta- (H2Bz4mT) and N(4)-para- (H2Bz4pT) tolyl-thiosemicarbazones derived from 2-benzoylpyridine. The free thiosemicarbazones proved to be highly cytotoxic against Jurkat, HL60 and the resistant HL60.Bcl-X(L) leukemia cell lines at nanomolar concentrations, but were much less cytotoxic to HepG2human hepatoma cells. Upon coordination to palladium(II) the cytotoxic activity against all studied cell lines decreases. However, the high cytotoxicity of the free thiosemicarbazones against leukemia, together with their hepatotoxic profile similar to that of cisplatin suggest that N(4)-tolyl thiosemicarbazones have potential as chemotherapeutic drug candidates.