Effects of aurothiomalate and gold(III) complexes on spontaneous motility of isolated human oviduct.

Organic gold complexes have different biological activity, depending on their potential for interactions with key functional molecules.The aim of this study was to investigate potential of several newly synthesized organic gold complexes to influence spontaneous motility of the Fallopian tubes.The effects of [Au(bipy)Cl(2)](+) (dichloride(2,2'-bipyridyl)aurate(III)-ion), aurothiomalate, [Au(DMSO)(2)Cl(2)]Cl and DMSO on spontaneous motility of Fallopian tubes were tested on the isolated tube segments in vitro. Aurothiomalate (from 2.9 × 10(-9) to 4.9 × 10(-4) M/l), [Au(bipy)Cl(2)]Cl (from 3.3 × 10(-9) to 4.2 × 10(-5) M/l) and DMSO (from 1.9 × 10(-8) to 1.0 × 10(-5) M/l) did not affect spontaneous contractions of the isolated Fallopian tube ampulla, while [Au(DMSO)(2)Cl(2)]Cl (from 2.9 × 10(-9) to 4.2 × 10(-5) M/l) showed concentration-dependent increase (stimulation) of spontaneous contractions of the isolated Fallopian tube isthmus, and remained without effect on the isolated ampulla.The drugs designed as organic gold complexes with weaker bonds between the gold itself and organic part of a molecule could adversely affect motility of the Fallopian tubes, and theoretically fertility of women taking such drugs in their reproductive age.

Kinetics and mechanism of the reactions of Au(III) complexes with some biologically relevant molecules.

The kinetics of the substitution reactions between the mono-functional Au(III) complexes, [Au(dien)Cl](2+) and [Au(terpy)Cl](2+) (dien = 3-azapentane-1,5-diamine, terpy = 2,2';6',2''-terpyridine) and bi-functional Au(III) complexes, [Au(bipy)Cl(2)](+) and [Au(dach)Cl(2)](+) (bipy = 2.2'-bipyridine, dach = (1R,2R)-1,2-diaminocyclohexane) and biologically relevant ligands such as l-histidine (l-His), inosine (Ino), inosine-5'-monophosphate (5'-IMP) and guanosine-5'-monophosphate (5'-GMP), were studied in detail. All kinetic studies were performed in 25 mM Hepes buffer (pH = 7.2) in the presence of NaCl to prevent the spontaneous hydrolysis of the chloride complexes. The reactions were followed under pseudo-first order conditions as a function of ligand concentration and temperature using stopped-flow UV-vis spectrophotometry. The results showed that the mono-functional complexes react faster than the bi-functional complexes in all studied reactions. The [Au(terpy)Cl](2+) complex is more reactive than the [Au(dien)Cl](2+) complex, which was confirmed by quantum chemical (DFT) calculations. A more than 50% lower activation energy for the terpy than for the dien based complex was found. The bi-functional [Au(bipy)Cl(2)](+) complex is more reactive than the [Au(dach)Cl(2)](+) complex. The reactivity of the studied nucleophiles follows the same order for all studied systems, viz. l-His > 5'-GMP > 5'-IMP > Ino. According to the measured activation parameters, all studied reactions follow an associative substitution mechanism. Quantum chemical calculations (B3LYP/LANL2DZp) suggest that ligand substitution in [Au(terpy)Cl](2+) and [Au(dien)Cl](2+) by imidazole follows an interchange mechanism with a significant degree of associative character. The results demonstrate the strong connection between the reactivity of the complexes toward biologically relevant ligands and their structural and electronic characteristics. Therefore, the binding of gold(III) complexes to 5'-GMP, constituent of DNA, is of particular interest since this interaction is thought to be responsible for their anti-tumour activity.

Cytotoxicity of gold(III) complexes on A549 human lung carcinoma epithelial cell line.

We have studied the kinetics of the complex formation of gold(III) complexes, [Au(en)Cl2]+ (dichlorido( ethylendiamine)aurate(III)-ion) [Au(dach)Cl2] (dichloride(1,2-diaminocyclohexane)aurate(III)-ion) and [Au(bipy)Cl2]+ (dichlorido(2,2'-bipyridyl)aurate(III)-ion) with guanosine5'-monophosphate (5'-GMP). It was shown that 5'-GMP have a high affinity for gold(III) complex, which may have important biological implications, since the interactions of Au(III) with DNA are thought to be responsible for the anti-tumor activity. The [Au(bipy)Cl2]+ complex is more reactive than [Au(en)Cl2]+ or [Au(dach)Cl2]+. The activation parameters for all studied reactions suggest an associative substitution mechanism. The cytotoxicity of gold(III) complexes was tested on A549 human lung carcinoma epithelial cell line and was evaluated by cytotoxic (MTT and LDH test) and apoptotic assays. The results showed that all tested gold(III) complexes displayed cytotoxic effect on A549 cells. Among the tested gold (III) complexes, AuBIPY showed the best cytotoxic effects.

Ligand substitution reactions and cytotoxic properties of [Au(L)Cl2](+) and [AuCl2(DMSO)2]+ complexes (L=ethylenediamine and S-methyl-l-cysteine).

We have studied the kinetics of the complex formation of gold(III) complexes, [AuCl(2)(en)](+) (dichlorido(ethylenediamine)aurate(III)-ion) and [AuCl(2)(SMC)] (dichlorido (S-methyl-l-cysteine)aurate(III)) with four biologically N-donor nucleophiles. It was shown that studied ligands have a high affinity for gold(III) complex, which may have important biological implications, since the interactions of Au(III) with DNA is thought to be responsible for the anti-tumour activity. The [AuCl(2)(SMC)] complex is more reactive than [AuCl(2)(en)](+). L-His reacts faster than the other N-donor nucleophiles in the reaction with [AuCl(2)(en)](+), but in the reaction with [AuCl(2)(SMC)] 5'-GMP is the best nucleophile. Gold(III) complexes are much more reactive than Pt(II) complexes with the same nucleophiles. The activation parameters for all studied reactions suggest an associative substitution mechanism. The cytotoxicity of gold(III) complexes, [AuCl(2)(en)](+), [AuCl(2)(SMC)] and [AuCl(2)(DMSO)(2)](+) was evaluated in vitro against chronic lymphocytic leukemia cells, obtained from blood of patients with chronic lymphocytic leukemia (CLL). The [AuCl(2)(en)](+) complex show comparable cytotoxicity profiles compared to cisplatin.