New gold(III) complexes TGS 121, 404, and 702 show anti-tumor activity in colitis-induced colorectal cancer: an in vitro and in vivo study.

BACKGROUND: Chronic inflammation in the course of inflammatory bowel disease may result in colon cancer, or colitis-associated colorectal cancer (CACRC). It is well established that CACRC is associated with oxidative stress and secretion of multiple pro-inflammatory cytokines, e.g. tumor necrosis factor-α. Recently, we proved that the administration of gold(III) complexes resulted in the alleviation of acute colitis in mice. The aim of the current study was to assess the antitumor effect of a novel series of gold(III) complexes: TGS 121, 404, 512, 701, 702, and 703. MATERIALS: Analyzed gold(III) complexes were screened in the in vitro studies using colorectal cancer and normal colon epithelium cell lines, SW480, HT-29, and CCD 841 CoN, and in vivo, in the CACRC mouse model. RESULTS: Of all tested complexes, TGS 121, 404, and 702 exhibited the strongest anti-tumor effect in in vitro viability assay of colon cancer cell lines and in in vivo CACRC model, in which these complexes decreased the total number of colonic tumors and macroscopic score. We also evidenced that the mechanism of action was linked to the enzymatic antioxidant system and inflammatory cytokines. CONCLUSIONS: TGS 121, 404, and 702 present anti-tumor potential and are an attractive therapeutic option for colorectal cancer.

A New Gold(III) Complex, TGS 703, Shows Potent Anti-Inflammatory Activity in Colitis via the Enzymatic and Non-Enzymatic Antioxidant System-An In Vitro, In Silico, and In Vivo Study.

Inflammatory bowel diseases (IBD) and their main representatives, Crohn's disease and ulcerative colitis, are worldwide health-care problems with constantly increasing frequency and still not fully understood pathogenesis. IBD treatment involves drugs such as corticosteroids, derivatives of 5-aminosalicylic acid, thiopurines, and others, with the goal to achieve and maintain remission of the disease. Nowadays, as our knowledge about IBD is continually growing, more specific and effective therapies at the molecular level are wanted. In our study, we tested novel gold complexes and their potential effect on inflammation and IBD in vitro, in silico, and in vivo. A series of new gold(III) complexes (TGS 404, 512, 701, 702, and 703) were designed and screened in the in vitro inflammation studies. In silico modeling was used to study the gold complexes' structure vs. their activity and stability. Dextran sulphate sodium (DSS)-induced mouse model of colitis was employed to characterize the anti-inflammatory activity in vivo. Lipopolysaccharide (LPS)-stimulated RAW264.7 cell experiments proved the anti-inflammatory potential of all tested complexes. Selected on the bases of in vitro and in silico analyses, TGS 703 significantly alleviated inflammation in the DSS-induced mouse model of colitis, which was confirmed by a statistically significant decrease in the macro- and microscopic score of inflammation. The mechanism of action of TGS 703 was linked to the enzymatic and non-enzymatic antioxidant systems. TGS 703 and other gold(III) complexes present anti-inflammatory potential and may be applied therapeutically in the treatment of IBD.

New gold (III) cyanide complex TGS 121 induces ER stress, proteasome inhibition and death of Ras-hyperactivated cells.

Metal-based agents in cancer therapy, like cisplatin and its derivates, have established clinical applications but also can induce serious side effects. Thus, metallotherapeutic alternatives for platinum derivatives are developed and intensively studied. Platinum is replaced by several transition metals including gold. Especially gold (III) complexes can have the same square-planar structure and are isoelectric with platinum (II). Hence, they are developed as potential anti-cancer drugs. Thus, our group projected and developed a group of novel cyanide-based gold (III) complexes. Within this work, we aimed to characterize the safety and effectivity of one of them, TGS 121. TGS 121 in our preliminary work was selective for Ras-hyperactivated cells. Here we studied the effects of the novel complex in cancerous Ras-3 T3 and non-cancerous NIH-3 T3 cells. The complex TGS 121 turned out to be non-toxic for NIH-3 T3 cells and to induce death and alternations in Ras-hyperactivated cells. We found induction of ER stress, mitochondria swelling, proteasome inhibition, and cell cycle block. Moreover, TGS 121 inhibited cell migration and induced the accumulation of perinuclear organelles that was secondary to proteasome inhibition. Results presented in this report suggest that stable gold-cyanide TGS 121 complex is non-toxic, with a targeted mechanism of action and it is promising in anticancer drug discovery.

Gold (III) Derivatives in Colon Cancer Treatment.

Cancer is one of the leading causes of morbidity and mortality worldwide. Colorectal cancer (CRC) is the third most frequently diagnosed cancer in men and the second in women. Standard patterns of antitumor therapy, including cisplatin, are ineffective due to their lack of specificity for tumor cells, development of drug resistance, and severe side effects. For this reason, new methods and strategies for CRC treatment are urgently needed. Current research includes novel platinum (Pt)- and other metal-based drugs such as gold (Au), silver (Ag), iridium (Ir), or ruthenium (Ru). Au(III) compounds are promising drug candidates for CRC treatment due to their structural similarity to Pt(II). Their advantage is their relatively good solubility in water, but their disadvantage is an unsatisfactory stability under physiological conditions. Due to these limitations, work is still underway to improve the formula of Au(III) complexes by combining with various types of ligands capable of stabilizing the Au(III) cation and preventing its reduction under physiological conditions. This review summarizes the achievements in the field of stable Au(III) complexes with potential cytotoxic activity restricted to cancer cells. Moreover, it has been shown that not nucleic acids but various protein structures such as thioredoxin reductase (TrxR) mediate the antitumor effects of Au derivatives. The state of the art of the in vivo studies so far conducted is also described.

New Class of Anti-Inflammatory Therapeutics Based on Gold (III) Complexes in Intestinal Inflammation-Proof of Concept Based on In Vitro and In Vivo Studies.

Inflammatory bowel diseases (IBD) are at the top of the worldwide rankings for gastrointestinal diseases as regards occurrence, yet efficient and side-effect-free treatments are currently unavailable. In the current study, we proposed a new concept for anti-inflammatory treatment based on gold (III) complexes. A new gold (III) complex TGS 121 was designed and screened in the in vitro studies using a mouse macrophage cell line, RAW264.7, and in vivo, in the dextran sulphate sodium (DSS)-induced mouse model of colitis. Physicochemical studies showed that TGS 121 was highly water-soluble; it was stable in water, blood, and lymph, and impervious to sunlight. In lipopolysaccharide (LPS)-stimulated RAW264.7 cells, the complex showed a potent anti-inflammatory profile, as evidenced in neutral red uptake and Griess tests. In the DSS-induced mouse model of colitis, the complex administered in two doses (1.68 µg/kg, intragastrically, and 16.8 µg/kg, intragastrically, once daily) produced a significant (* p < 0.05) anti-inflammatory effect, as shown by macroscopic score. The mechanism of action of TGS 121 was related to the enzymatic and non-enzymatic antioxidant system; moreover, TGS 121 induced changes in the tight junction complexes expression in the intestinal wall. This is the first study proving that gold (III) complexes may have therapeutic potential in the treatment of IBD.

Energetics of interactions in the solid state of 2-hydroxy-8-X-quinoline derivatives (X = Cl, Br, I, S-Ph): comparison of Hirshfeld atom, X-ray wavefunction and multipole refinements.

In this work, two methods of high-resolution X-ray data refinement: multipole refinement (MM) and Hirshfeld atom refinement (HAR) - together with X-ray wavefunction refinement (XWR) - are applied to investigate the refinement of positions and anisotropic thermal motion of hydrogen atoms, experiment-based reconstruction of electron density, refinement of anharmonic thermal vibrations, as well as the effects of excluding the weakest reflections in the refinement. The study is based on X-ray data sets of varying quality collected for the crystals of four quinoline derivatives with Cl, Br, I atoms and the -S-Ph group as substituents. Energetic investigations are performed, comprising the calculation of the energy of intermolecular interactions, cohesive and geometrical relaxation energy. The results obtained for experimentally derived structures are verified against the values calculated for structures optimized using dispersion-corrected periodic density functional theory. For the high-quality data sets (the Cl and -S-Ph compounds), both MM and XWR could be successfully used to refine the atomic displacement parameters and the positions of hydrogen atoms; however, the bond lengths obtained with XWR were more precise and closer to the theoretical values. In the application to the more challenging data sets (the Br and I compounds), only XWR enabled free refinement of hydrogen atom geometrical parameters, nevertheless, the results clearly showed poor data quality. For both refinement methods, the energy values (intermolecular interactions, cohesive and relaxation) calculated for the experimental structures were in similar agreement with the values associated with the optimized structures - the most significant divergences were observed when experimental geometries were biased by poor data quality. XWR was found to be more robust in avoiding incorrect distortions of the reconstructed electron density as a result of data quality issues. Based on the problem of anharmonic thermal motion refinement, this study reveals that for the most correct interpretation of the obtained results, it is necessary to use the complete data set, including the weak reflections in order to draw conclusions.

Fullerene Derivatives of Nucleoside HIV Reverse Transcriptase Inhibitors-In Silico Activity Prediction.

Here we present new derivatives of nucleoside reverse transcriptase inhibitors with a C20 fullerene. The computational chemistry methods used in this study evaluate affinity of designed compounds towards the HIV-1 reverse transcriptase (RT) binding site and select the most active ones. The best of the designed compounds have superior or similar affinity to RT active site in comparison to most active test compounds, including drugs used in anti-HIV therapy.

Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression.

Depression is nowadays a major contributor to global burden of disease. The most commonly prescribed drugs influence monoaminergic pathways, mainly concentrating on serotonin. Unfortunately, there are several drawbacks associated with these drugs, namely late onset of action, risk of suicide and adverse effects: mainly nausea, vomiting and sexual dysfunction. Therefore there is still need for new drugs with possibly high efficacy and fewer side effects. In this paper selected compounds which inhibit serotonin reuptake by acting on the serotonin transporter (SERT) and various serotoninergic receptors are presented. We also discuss the ways in which their mechanism of action can be modified to improve pharmacological profile. Here, we focus on describing drugs' potency, efficacy and adverse effects. Additional applications, apart from depression, are also discussed.

Adsorption of Antifungal Drugs Inside Pristine and Functionalized Fullerenes and Nanotubes: DFT Investigation.

BACKGROUND: Econazole, sulconazole and tioconazole usage as antifungal agents is limited due to poor pharmacokinetic properties. Pristine and hydroxylated structures of the C240 fullerene and single walled carbon nanotube (SWCNT) were proposed as transporters of these imidazoles potentially enhancing their pharmacokinetics. METHODS: To assess possibility of creation of the endohedral complexes of the azoles and carbon nanostructures, their adsorption and interaction energies were calculated with the hybrid exchange-correlation density functional B97-1 and 6-31(d,p) basis set. Interactions within the transporter - drug complexes were investigated with the Atoms in Molecules (AIM) Theory and Reduced Density Gradient (RDG). RESULTS AND CONCLUSIONS: The adsorption energies of the studied azoles depend on type and surface modification of the transporter. Hydroxylation of the fullerene and nanotube surface makes an opportunity for chemisorption of the investigated antifungal drugs. The pristine and hydroxylated nanotube complexes exhibit thermodynamic stability. The complexes of the fullerenes are thermodynamically unstable but its kinetic stability could be significant thus allowing for the such structures to exist. The energetic instability would enhance liberation of the encapsulated molecule from the complex. It is advantageous in the context of drug release.

Cytisine basicity, solvation, logP, and logD theoretical determination as tool for bioavailability prediction.

Cytisine, an α4ß2 nicotinic receptor partial agonist, is a plant alkaloid widely used as a smoking cessation agent. Despite long history of use, knowledge on pharmacokinetics of cytisine still demands an extension. This work is aimed at theoretical determination of physicochemical parameters that affect the bioavailability of cytisine. The acidic dissociation constant, Gibbs free energy of solvation in water and n-octanol as well as n-octanol/water partition coefficient and n-octanol/water distribution coefficient of cytisine were calculated as quantities corresponding to its solubility and permeability. Cytisine structure was optimized with several quantum chemical methods-ab initio: HF and MP2, and DFT functionals (B3LYP, B3LYP-D3, CAM-B3LYP, M06-2X, TPSS, VSXC) with 6-311++G(d,p) basis set. Solvation of cytisine in water and n-octanol was determined with the SMD continuum model. It was shown that lipophilicity of cytisine depends on the pH of an environment. Protonated cytisine, the most populated state under acidic conditions, is characterized by enhanced hydrophilicity. Then neutral cytisine, dominating in a basic environment, demonstrates more lipophilic character. It appears that cytisine is very well soluble in the gastrointestinal (GI) tract fluids. Then the distribution of cytisine ought to occur very rapidly. However, permeability of cytisine through the mucous membrane of the GI tract may be limited, leading to the diminished bioavailability.

Synthesis and anticancer activity of 7-hydroxycoumarinyl gallates.

BACKGROUND: The search for anti-cancer agents includes naturally occurring substances and theirs modifications. Therefore we invented and designed compounds that represent fused derivatives of gallic acid with coumarins. METHODS: As a result, a series of 8 novel esters of gallic acid and 7-hydroxycoumarins were synthesized and evaluated for anticancer activity. The structures of the compounds were established by IR, (1)H, (13)C NMR and HR MS spectra. The esters were assayed for antiproliferative activity against human leukemia HL-60 and prostate cancer DU145 cell lines. The activity of novel esters was evaluated by cell viability assays as well as by analysis of cell cycle and cell death mechanism. RESULTS: The esters were found to be of similar or higher activity than gallic acid. No pronounced harmful effect was observed in non-cancer cells. CONCLUSIONS: The novel compounds represent an excellent starting point for the further optimization and the design of therapeutically effective anti-cancerous drugs.