ABSTRACT
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).
Subject(s)
Antineoplastic Agents/pharmacology , Coordination Complexes/pharmacology , DNA Topoisomerases, Type I/metabolism , Enzyme Inhibitors/pharmacology , Pyridines/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Thiosemicarbazones/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Coordination Complexes/chemical synthesis , Coordination Complexes/chemistry , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Humans , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/metabolism , Thiosemicarbazones/chemical synthesis , Thiosemicarbazones/chemistryABSTRACT
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.
Subject(s)
Coordination Complexes/chemistry , Enzyme Inhibitors/pharmacology , Glutathione Reductase/antagonists & inhibitors , Organometallic Compounds/pharmacology , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Thiosemicarbazones/chemistry , Animals , Cell Survival/drug effects , Chlorocebus aethiops , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HT29 Cells , Humans , Liver/enzymology , MCF-7 Cells , Models, Molecular , Molecular Structure , Organometallic Compounds/chemical synthesis , Organometallic Compounds/chemistry , Rats , Structure-Activity Relationship , Thioredoxin-Disulfide Reductase/metabolism , Vero CellsABSTRACT
2-Acetylpyridine-phenylhydrazone (H2AcPh), its para-chlorophenylhydrazone (H2AcpClPh) and para-nitrophenylhydrazone (H2AcpNO(2)Ph) analogues, the corresponding 2-benzoylpyridine-derived hydrazones (H2BzPh, H2BzpClPh and H2BzpNO(2)Ph) and their gallium(III) complexes were assayed for their cytotoxic activity against U87 (expressing wild-type p53 protein) and T98 (expressing mutant p53 protein) glioma cells. IC(50) values against both glioma cells and against the MRC5 (human fetal lung fibroblast) lineage were obtained for the hydrazones, but not for their gallium(III) complexes, due to their low solubility. Hydrazones were highly cytotoxic at nanomolar doses against U87 and T98 cells. The therapeutic indexes (TI = IC(50MRC5)/IC(50glioma)) were 2-660 for T98 cells and 28-5000 for U87 cells, indicating that the studied hydrazones could be good antitumor drug candidates to treat brain tumors.
Subject(s)
Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Gallium/chemistry , Glioma/drug therapy , Glioma/pathology , Hydrazones/chemistry , Pyridines/chemistry , Brain Neoplasms/drug therapy , Brain Neoplasms/pathology , Cell Proliferation/drug effects , Cells, Cultured , Crystallography, X-Ray , Fetus/cytology , Fetus/metabolism , Fibroblasts/cytology , Fibroblasts/metabolism , Humans , Lung/cytology , Lung/metabolism , Models, Molecular , Molecular Structure , Quantitative Structure-Activity RelationshipABSTRACT
Complex [Bi(Lp)(2)]Cl was obtained with 4-hydroxy-3-(3-methylbut-2-enyl)naphthalene-1,2-dione, "lapachol" (HLp). Lapachol, [Bi(Lp)(2)]Cl and BiCl(3) were evaluated in a murine model of inflammatory angiogenesis induced by subcutaneous implantation of polyether polyurethane sponge discs. Intraperitoneal (i.p.) administration of lapachol or [Bi(Lp)(2)]Cl reduced the hemoglobin content in the implants suggesting that reduction of neo-vascularization was caused by lapachol. In the per os treatment only [Bi(Lp)(2)]Cl decreased the hemoglobin content in the implants. Likewise, N-acetylglucosaminidase (NAG) activity decreased in the implants of the groups i.p. treated with lapachol and [Bi(Lp)(2)]Cl while in the per os treatment inhibition was observed only for [Bi(Lp)(2)]Cl. Histological analysis showed that the components of the fibro-vascular tissue (vascularization and inflammatory cell population) were decreased in lapachol- and complex-treated groups. Our results suggest that both lapachol and [Bi(Lp)(2)]Cl exhibit anti-angiogenic and anti-inflammatory activities which have been attributed to the presence of the lapachol ligand. However, coordination to bismuth(III) could be an interesting strategy for improvement of lapachol's therapeutic properties.
Subject(s)
Angiogenesis Inhibitors , Anti-Inflammatory Agents , Bismuth/chemistry , Naphthoquinones , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/therapeutic use , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/therapeutic use , Implants, Experimental , Inflammation/drug therapy , Male , Mice , Molecular Structure , Naphthoquinones/chemistry , Naphthoquinones/therapeutic useABSTRACT
Salicylaldehyde 2-chlorobenzoyl hydrazone (H(2)LASSBio-466), salicylaldehyde 4-chlorobenzoyl hydrazone (H(2)LASSBio-1064) and their complexes [Zn(LASSBio-466)H(2)O](2) (1) and [Zn(HLASSBio-1064)Cl](2) (2) were evaluated in animal models of peripheral and central nociception, and acute inflammation. All studied compounds significantly inhibited acetic acid-induced writhing response. Upon coordination the anti-nociceptive activity was favored in the complex 1. H(2)LASSBio-466 inhibited only the first phase of the formalin test, while 1 was active in the second phase, like indomethacin, indicating its ability to inhibit nociception associated with the inflammatory response. Hence coordination to zinc(II) altered the pharmacological profile of H(2)LASSBio-466. H(2)LASSBio-1064 inhibited both phases but this effect was not improved by coordination. The studied compounds did not increase the latency of response in the hot plate model, indicating their lack of central anti-nociceptive activity. All compounds showed levels of inhibition of zymosan-induced peritonitis comparable or superior to indomethacin, indicating an expressive anti-inflammatory profile.
Subject(s)
Aldehydes/chemistry , Analgesics/pharmacology , Anti-Inflammatory Agents/pharmacology , Coordination Complexes/pharmacology , Hydrazones/chemistry , Inflammation/drug therapy , Pain , Peritonitis/drug therapy , Acetic Acid/adverse effects , Analgesics/chemical synthesis , Animals , Anti-Inflammatory Agents/chemical synthesis , Coordination Complexes/chemical synthesis , Crystallography, X-Ray , Dipyrone/pharmacology , Female , Formaldehyde/adverse effects , Hot Temperature/adverse effects , Indomethacin/pharmacology , Inflammation/chemically induced , Inflammation/physiopathology , Magnetic Resonance Spectroscopy , Male , Mice , Morphine/pharmacology , Pain/chemically induced , Pain/drug therapy , Pain/physiopathology , Pain/prevention & control , Pain Measurement , Peritonitis/chemically induced , Peritonitis/physiopathology , Zinc/metabolism , Zymosan/adverse effectsABSTRACT
[(n-Bu)Sn(2Ac4oClPh)Cl2] (1), [(n-Bu)Sn(2Ac4oFPh)Cl2] (2), [(n-Bu)Sn(2Ac4oNO2Ph)Cl2] (3), [(n-Bu)Sn(2Bz4oClPh)Cl2] (4), [(n-Bu)Sn(2Bz4oFPh)Cl2] (5) and [(n-Bu)Sn(2Bz4oNO2Ph)Cl2] (6) were obtained by reacting [(n-Bu)SnCl3] with 2-acetylpyridine-N4-orthochlorophenyl thiosemicarbazone (H2Ac4oClPh), 2-acetylpyridine-N4-orthofluorphenyl thiosemicarbazone (H2Ac4oFPh), 2-acetylpyridine-N4-orthonitrophenyl thiosemicarbazone (H2Ac4oNO2Ph), and with the corresponding 2-benzoylpyridine-derived thiosemicarbazones (H2Bz4oClPh, H2ABz4oFPh and H2Bz4oNO2Ph). The antifungal activity of the studied compounds was evaluated against several Candida species. Upon coordination of H2Bz4oNO2Ph to tin in complex (6) the antifungal activity increased three times against Candida albicans and Candida krusei and six times against Candida glabrata and Candida parapsilosis. The minimum inhibitory concentration (MIC) values of H2Ac4oNO2Ph and its complex (3) against C. albicans, C. parapsilosis and C. glabrata are similar to that of fluconazole. All studied compounds were more active than fluconazole against C. krusei.