Evaluation of reproductive toxicity in male rats treated with novel synthesized ruthenium(II) and gold(I)-NHC complexes.

In this study, we aimed to determine the reproductive toxicity in rat induced by ruthenium(II)-NHC (Ru(II)) and gold(I)-NHC (Au(I)) complexes that have anticarcinogenic effects. For this purpose, 35 Sprague-Dawley rats were randomly divided into 5 equal groups. In control group, rats treated with saline, Ru(II), and Au(I) complexes were intraperitoneally given high (10 mg/kg) and low (5 mg/kg) doses to rats via a one-time administration. The animals were sacrificed, and testis tissues were taken on Day 10 of the drug administration for the determination of the biochemical, histopathological, spermatological, and hormonal parameters. It was determined that treatment group that was subjected to treatment using both Ru(II) and Au(I) complexes significantly caused oxidative, histopathological, spermatological, and hormonal damage compared to control group. However, the sexual and accessory organ weight did not significantly change when compared to control. In addition, it was shown that Au(I) treatment generally caused more adverse effects than Ru(II) treatment in a dose-dependent manner. In conclusion, when these synthesized compounds are used for the treatment of cancer, they could cause toxic effects on male reproductive system and lead to infertility. However, Ru(II) complex is a more preferable option in cancer treatment, particularly in terms of user safety.

An Erlotinib gold(I) conjugate for combating triple-negative breast cancer.

An Erlotinib triphenylphosphane gold(I) conjugate has been prepared from AuCl(PPh3) and its crystal structure has been established by X-ray diffraction, showing a metallo-helicate formation. IC50 values of the new gold conjugate were calculated towards a panel of human tumor cell lines representative of breast (MCF-7, MDA-MB-231) and colon (HT-29) cancer cells. Overall, the gold conjugate exhibited higher cytotoxic activity than that of Erlotinib against the cancer cells studied. Particularly, the antiproliferative effect of the conjugate demonstrated to be 68-fold higher than Erlotinib in highly metastatic and triple negative MDA-MB-231 cell line. The gold conjugate caused DNA damage, reactive oxygen species (ROS) increase and induced apoptosis. Flow cytometry analysis showed that the conjugate induces significant arrest in S and G2/M phases primarily, whereas Erlotinib, as an inhibitor of epidermal growth factor receptor (EGFR), blocks G1/S transition and increases G1 cell population.

Assembly behavior of amylin fragment hIAPP19-37 regulated by Au(III) complexes.

Human islet amyloid polypeptide (hIAPP, amylin) may self-aggregate and rupture the membrane of ß cells, which is closely correlated with the pathogenesis of type 2 diabetes mellitus (T2DM). Hence, suppressing amyloidogenic hIAPP may be beneficial for the treatment of diabetes. As an important part of hIAPP, the fragment hIAPP19-37 was studied in this work to explore their disaggregation and cellular behavior regulation by some selected Au complexes, as follows: dichloro diethyl dithiocarbamate Au complex [AuCl2(DDTC)] (1), dichloro pyrrolidine dithiocarbamate Au complex [AuCl2(PDT)] (2), dichloro 4-4'-dimethyl-2,2'-bipyridyl Au(III) chloride [AuCl2(Me)2bpy]Cl (3), and dichloro 4-4-di-tert-butyl-2,2'-bipyridyl Au(III) chloride [AuCl2(t-Bu)2bpy]Cl (4). The peptide aggregation was observed and analyzed by fluorescence assay, atomic force microscopy (AFM), dynamic light scattering (DLS) and other methods. The assembly behaviors of hIAPP19-37 affected by the four Au complexes indicated that these complexes could effectively inhibit the fibrillation of the peptide and depolymerized the aged peptide into nanoscale particles. These Au compounds also remarkably reduced membrane leakage and cytotoxicity caused by peptide oligomers. An interaction study revealed that the complexes were predominantly bound with hIAPP19-37 through hydrophobic and electrostatic interactions, and metal coordination. The differences among various complexes were compared according to their binding affinity, inhibitory effect, and cellular behavior. Our study offers a potential path for the possible utilization of Au compounds as amyloidosis inhibitors.

In vitro antitumour and hepatotoxicity profiles of Au(I) and Ag(I) bidentate pyridyl phosphine complexes and relationships to cellular uptake.

In this study we characterised the in vitro antitumour and hepatotoxicity profiles of a series of Au(I) and Ag(I) bidentate phenyl and pyridyl complexes in a panel of cisplatin-resistant human ovarian cancer cell-lines, and in isolated rat hepatocytes. The gold and silver compounds overcame cisplatin-resistance in the CH1-cisR, 41M-cisR and SKOV-3 cell-lines, and showed cytotoxic potencies strongly correlated with their lipophilicity. Complexes with phenyl or 2-pyridyl ligands had high antitumour and hepatotoxic potency and low selectivity between different cell-lines. Their cytotoxicity profiles were similar to classic mitochondrial poisons and an example of this type of compound was shown to accumulate preferentially in the mitochondria of cancer cells in a manner that depended upon the mitochondrial membrane potential. In contrast, complexes with 3- or 4-pyridyl ligands had low antitumour and hepatotoxic potency and cytotoxicity profiles similar to 2-deoxy-D-glucose. In addition, they showed high selectivity between different cell-lines that was not attributable to variation in uptake in different cell-types. The in vitro hepatotoxic potency of the series of gold and silver compounds varied by over 61-fold and was closely related to their lipophilicity and hepatocyte uptake. In conclusion, Au(I) and Ag(I) bidendate pyridyl phosphine complexes demonstrate activity against cisplatin-resistant human cancer cells and in vitro cytotoxicity that strongly depends upon their lipophilicity.

Anticancer Gold N-Heterocyclic Carbene Complexes: A Comparative in†vitro and ex†vivo Study.

A series of organometallic AuI N-heterocyclic carbene (NHC) complexes was synthesized and characterized for anticancer activity in four human cancer cell lines. The compounds' toxicity in healthy tissue was determined using precision-cut kidney slices (PCKS) as a tool to determine the potential selectivity of the gold complexes ex vivo. All evaluated compounds presented cytotoxic activity toward the cancer cells in the nano- or low micromolar range. The mixed AuI NHC complex, (tert-butylethynyl)-1,3-bis-(2,6-diisopropylphenyl)imidazol-2-ylidene gold(I), bearing an alkynyl moiety as ancillary ligand, showed high cytotoxicity in cancer cells in vitro, while being barely toxic in healthy rat kidney tissues. The obtained results open new perspectives toward the design of mixed NHC-alkynyl gold complexes for cancer therapy.

Gold(III) complexes with hydroxyquinoline, aminoquinoline and quinoline ligands: Synthesis, cytotoxicity, DNA and protein binding studies.

In this article, we report on the synthesis and the chemical and biological characterization of novel gold(III) complexes based on hydroxyl- or amino-quinoline ligands that are evaluated as prospective anticancer agents. To gain further insight into their reactivity and possible mode of action, their interactions with model proteins and standard nucleic acid molecules were investigated.

Effects of nanoparticle size and gestational age on maternal biodistribution and toxicity of gold nanoparticles in pregnant mice.

Gold nanoparticles (GNPs) have considerable applications in biomedicine, such as in bio-sensing, bio-imaging, drug delivery and photothermal therapeutics. However, currently there are limited information regarding the impact of pregnancy on their biodistribution, elimination and toxicity. In this study, we investigated the biodistribution and potential toxic effects of different-sized GNPs (1.5, 4.5, 13, 30 and 70 nm in diameter) in non-pregnant and pregnant mice at different gestational ages (E5.5, 7.5, 9.5, 11.5 and 13.5). 5h after intravenous injection, GNPs exhibited size-dependent biodistribution profiles; however, regardless of size, no significant biodistribution changes were observed between non-pregnant and pregnant mice. Kinetic studies showed that 4.5 nm GNPs were primarily excreted through urine within 5h, whereas 30 nm GNPs had a more prolonged blood circulation time. No apparent toxic effects (e.g., increased mortality, altered behavior, reduced animal weight, abnormal organ morphology or reduced pregnancy duration) were observed with different-sized GNPs in pregnant mice. However, treatment with 30 nm GNPs induced mild emphysema-like changes in lungs of pregnant mice. These results indicated that the maternal biodistribution patterns of GNPs in pregnant mice depended on particle size, but not gestational age; organ-specific adverse effects may arise with treatment with some GNPs according to their size.

Histological changes in kidney and liver of rats due to gold (III) compound [Au(en)Cl(2)]Cl.

INTRODUCTION: Development of novel metallodrugs with enhanced anti-proliferative potential and reduced toxicity has become the prime focus of the evolving medicinal chemistry. In this regards, gold (III) complexes with various ligands are being extensively investigated. In the current study renal and hepatic toxicity of a newly developed gold (III) compound [Au(en)Cl(2)]Cl was assessed by histopathological evaluation of liver and kidney specimens of rats exposed to the compound. METHODS: Male rats (n = 42) weighing 200-250 gram were injected single, varying doses of gold (III) compound [(dichlorido(ethylenediamine)aurate((III)]chloride [Au(en)Cl(2)]Cl in the acute toxicity component of the study. In the sub-acute toxicity part, a dose of 32.2 mg/kg (equivalent to 1/10 of LD50) was administered intraperitoneally for 14 consecutive days before sacrificing the animals. After autopsy, the renal and hepatic tissues were preserved in buffered formalin. Processing of the samples was followed by histopathological evaluation. The results were compared with the normal controls (n = 11). RESULTS: A dose of 32.2 mg/kg (1/10 of LD(50)) revealed no renal tubular necrosis. The predominant histopathological finding was mild pyelitis, a prominence of eosinophils and mild congestion. The hepatic lesions comprised varying extents of ballooning degeneration with accompanying congestion and focal portal inflammation. CONCLUSION: Gold (III) compound [Au(en)Cl(2)]Cl causes minimal histological changes in kidney and liver of rats, reflecting its relative safety as compared to other clinically established antineoplastic drugs.

Cytotoxic gold compounds: synthesis, biological characterization and investigation of their inhibition properties of the zinc finger protein PARP-1.

The new gold(III) complexes: [Au{2-(2'-pyridyl)imidazolate}Cl(2)] and [Au{2,6-bis(2'-benzimidazolate)pyridine}(OCOCH(3))] and the mono- and binuclear gold(I) complexes: [Au{2-(2'-pyridyl)imidazole}(PPh(3))](PF(6)), [Au(2-phenylimidazolate)(DAPTA)] (DAPTA = 3,7-diacetyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane), [(PPh(3)Au)(2)(2-R-imidazolate)](PF(6)) (R = 2-C(5)H(4)N, Ph) have been synthesized and characterized. The structure of the [(PPh(3)Au)(2){2-(2'-pyridyl)imidazolate)](PF(6)) complex was also characterized by X-ray crystallography. The antiproliferative properties of the complexes were assayed against human ovarian carcinoma cell lines, either sensitive (A2780) or resistant to cisplatin (A2780cisR), human mammary carcinoma cells (MCF7) and non-tumorigenic human kidney (HEK293) cells. Most of the studied compounds showed important cytotoxic effects. Interestingly, the compounds containing the 2-(2'-pyridyl)imidazolate ligand showed selectivity towards cancer cells with respect to the non-tumorigenic ones, with the dinuclear compound [(PPh(3)Au)(2){2-(2'-pyridyl)imidazolate)](PF(6)) being the most active. Some compounds were also screened for their inhibitory effect of the zinc-finger protein PARP-1, essential for DNA repair and relevant to the mechanisms of cancer cell resistance to cisplatin. Interaction studies of the compounds with the model protein ubiquitin were undertaken by electrospray ionization mass spectrometry (ESI MS). The results are discussed in relation to the putative mechanisms of action of the cytotoxic gold compounds.

A dual cytotoxic and anti-angiogenic water-soluble gold(III) complex induces endoplasmic reticulum damage in HeLa cells.

The water-soluble gold(III) complex [Au(III)(butyl-C^N)biguanide]Cl (butyl-HC^N = 2-(4-n-butylphenyl)pyridine, BCN) displays cytotoxicity through S-phase cell cycle arrest and endoplasmic reticulum (ER) damage in HeLa cells, and shows a promising anti-angiogenic effect at sub-cytotoxic concentrations.

Amides of gold(I) diphosphines prepared from N-heterocyclic sources and their in vitro and in vivo screening for anticancer activity.

A series of new neutral mononuclear or dinuclear gold(I) complexes and a cyclic cationic tetranuclear amidogold(I) complex comprising of the phosphines 1,2-bis(dimethylphosphino)ethane (dmpe), µ-1,2-bis(diphenylphosphino)ethane (dppe), µ-1,3-bis(diphenylphosphino)propane (dppp), µ-1,5-bis(diphenylphosphino)pentane (dpppe), µ-1,6-bis(diphenylphosphino)hexane (dpph) or trimethylphosphine, and several N-heterocyclic ring systems (imidazolate, pyrazolate, 1,2,3-triazolate, 1,2,4-triazolate, pyrrolate, 9H-purine-9-ate or 9H-purine-6-amine-9-ate) as ligands, reveal intermolecular aurophilic interactions and 2D channels available for solvent molecules in some of their crystal structures. The antitumour activity of the acyclic gold(I) compounds is highly dependent on the substituents on the phosphorus atoms being highest for phenyl groups and lower for methyl groups. The activity of these compounds against selected cell lines is linked to the length of the carbon bridge between the two phosphorus atoms being highest with a bridge consisting of 5 or 6 carbons. Two compounds with the highest tumour specifities that contain dpppe and pyrazolate (a lipophilic compound) or 1,2,4-triazolate (a hydrophilic compound) induce an apoptotic cell death pathway and a maximum dose to Balb/C mice is tolerated.

Tumor cytotoxicity of 5,6-dimethyl-1,10-phenanthroline and its corresponding gold(III) complex.

A gold(III) complex possessing 5,6-dimethyl-1,10-phenanthroline (5,6DMP) was synthesized and fully characterized using standard spectroscopic techniques, as well as X-ray crystallography and elemental analysis. The complex [(5,6DMP)AuCl(2)][BF(4)] (2) was found to possess a distorted square planar geometry about the gold(III) center, commonplace for d(8) Au(III) cations possessing sterically un-hindered polypyridyl ligands. Compound 2 was evaluated for its potential use as an anticancer therapeutic. It was determined that the complex is stable in phosphate buffer over a 24-hour period, thought it does undergo rapid reduction in the presence of equimolar amounts of reduced glutathione (GSH) and ascorbic acid. The DNA binding and in vitro tumor cytotoxicity of the title compound 2 were also determined. It was found to undergo weak and reversible binding to calf thymus DNA, and was more cytotoxic towards a panel of human cancer cell lines than the commonly used chemotherapy agent cisplatin. Cytotoxicity experiments with the free 5,6DMP ligand indicate that the ligand has IC(50) values that are slightly lower than those observed for the gold complex (2), and coupled with the fact that the ligand appears to be released from the gold(III) metal center in reducing environments, this suggests the ligand itself may play an important role in the antitumor activity of the parent gold complex.

Gold(I) analogues of a platinum-acridine antitumor agent are only moderately cytotoxic but show potent activity against Mycobacterium tuberculosis.

Cationic gold(I) complexes containing 1-[2-(acridin-9-ylamino)ethyl]-1,3-dimethylthiourea (1), [AuL(1)](n+) (where L is Cl(-), Br(-), SCN(-), PEt(3), PPh(3), or 1), derived from a class of analogous platinum(II) antitumor agents, have been synthesized. Unlike platinum, gold does not form permanent adducts with DNA, and its complexes are 2 orders of magnitude less cytotoxic in non-small-cell lung cancer cells than the most active platinum-based agent. Instead, several gold analogues show submicromolar and selective antimicrobial activity against Mycobacterium tuberculosis.