Novel Copper (II) Complexes with Fluorine-Containing Reduced Schiff Base Ligands Showing Marked Cytotoxicity in the HepG2 Cancer Cell Line.

Several novel copper (II) complexes of reduced Schiff bases containing fluoride substituents were prepared and structurally characterized by single-crystal X-ray diffraction. The complexes exhibited diverse structures, with the central atom in distorted tetrahedral geometry. The biological effects of the products were evaluated, specifically their cytotoxicity, antimicrobial, and antiurease activities, as well as affinity for albumin (BSA) and DNA (ct-DNA). The complexes showed marked cytotoxic activities in the HepG2 hepatocellular carcinoma cell line, considerably higher than the standard cisplatin. The cytotoxicity depended significantly on the substitution pattern. The best activity was observed in the complex with a trifluoromethyl group in position 4 of the benzene ring-the dichloro[(±)-trans-N,N'-bis-(4-trifluoromethylbenzyl)-cyclohexane-1,2-diamine]copper (II) complex, whose activity (IC50 28.7 µM) was higher than that of the free ligand and markedly better than the activity of the standard cisplatin (IC50 336.8 µM). The same complex also showed the highest antimicrobial effect in vitro. The affinity of the complexes towards bovine serum albumin (BSA) and calf thymus DNA (ct-DNA) was established as well, indicating only marginal differences between the complexes. In addition, all complexes were shown to be excellent inhibitors of the enzyme urease, with the IC50 values in the lower micromolar region.

Quercetin decreases fructose drinking in model of fructose-induced insulin resistance. Unexpected uric acid and TBARS lowering effect of methyl cellulose vehicle and fructose combination.

The aim of this study was to improve insulin sensitivity in fructose-treated animals by ingestion of flavonoid quercetin. Several signs of insulin resistance have been developed in rats by drinking 10% fructose solution for 9 weeks. The effect of 6-week-gavage-administrated quercetin (20 mg/kg/day in 1% methyl cellulose solution) was monitored. Rats of the control groups received methyl cellulose vehicle as well. The most striking result of the quercetin treatment was the normalization of the fructose solution drinking to the level of drinking water intake. In addition, quercetin supplementation considerably decreased the plasma glucose and Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index in rats consuming fructose. Surprisingly, fructose ingestion did not elevate plasma uric acid, thiobarbituric acid reactive substances, nitrotyrosine, or advanced glycation end products fluorescence. Instead, a reduction of the above parameters was observed. In summary, these results indicate that quercetin supplementation reduces fructose drinking and decreases plasma glucose and the HOMA-IR index. Furthermore, methyl cellulose, in combination with fructose, causes uric acid - lowering, antioxidant and anti-glycation effects. Thus, methyl cellulose possibly shifts fructose metabolism in favor of the utilization of antioxidant features of fructose. Our results call for using methyl cellulose in sweetened beverages and other sweetened food.

Critical view on antimicrobial, antibiofilm and cytotoxic activities of quinazolin-4(3H)-one derived schiff bases and their Cu(II) complexes.

A series of nine 2,3-disubstituted-quinazolin-4(3H)-one derived Schiff bases and their three Cu(II) complexes was prepared and tested for their antimicrobial activities against reference strains Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 and resistant clinical isolates of methicillin-resistant S. aureus (MRSA) and vancomycin-resistant E. faecalis (VRE). All the substances were tested in vitro against Mycobacterium tuberculosis H37Ra ATCC 25177, M. kansasii DSM 44162 and M. smegmatis ATCC 700084. While anti-enterococcal and antimycobacterial activities were insignificant, 3-[(E)-(2-hydroxy-5-nitrobenzylidene)amino]-2-(2-hydroxy-5-nitrophenyl)-2,3-dihydroquinazolin-4(1H)-one (SB3) and its Cu(II) complex (SB3-Cu) demonstrated bacteriostatic antistaphylococcal activity. In addition, both compounds, as well as the other two prepared complexes, showed antibiofilm activity, which resulted in a reduction of biofilm formation and eradication of mature S. aureus biofilm by 80% even at concentrations lower than the values of their minimum inhibitory concentrations. In addition, the compounds were tested for their cytotoxic effect on the human monocytic leukemia cell line THP-1. The antileukemic efficiency was improved by the preparation of Cu(II) complexes from the corresponding non-chelated Schiff base ligands.

New Unnatural Gallotannins: A Way toward Green Antioxidants, Antimicrobials and Antibiofilm Agents.

Nature has been a source of inspiration for the development of new pharmaceutically active agents. A series of new unnatural gallotannins (GTs), derived from d-lyxose, d-ribose, l-rhamnose, d-mannose, and d-fructose have been designed and synthesized in order to study the protective and antimicrobial effects of synthetic polyphenols that are structurally related to plant-derived products. The structures of the new compounds were confirmed by various spectroscopic methods. Apart from spectral analysis, the antioxidant activity was evaluated by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging and iron reducing power (FRAP) assays. Antibacterial activity of compounds was tested in vitro against Staphylococcus aureus ATCC 29213, Enterococcus faecalis ATCC 29212 (reference and control strains), three methicillin-resistant isolates of S. aureus, and three isolates of vancomycin-resistant E. faecalis. For screening of antimycobacterial effect, a virulent isolate of Mycobacterium tuberculosis and two non-tuberculous mycobacteria were used. Furthermore, antibiofilm activity of structurally different GTs against S. aureus, and their ability to inhibit sortase A, were inspected. Experimental data revealed that the studied GTs are excellent antioxidants and radical-scavenging agents. The compounds exhibited only a moderate antibacterial effect against Gram-positive pathogens S. aureus and E. faecalis and were practically inactive against mycobacteria. However, they were efficient inhibitors and disruptors of S. aureus biofilms in sub-MIC concentrations, and interacted with the quorum-sensing system in Chromobacteriumviolaceum. Overall, these findings suggest that synthetic GTs could be considered as promising candidates for pharmacological, biomedical, consumer products, and for food industry applications.

Antioxidant, Cytotoxic, Genotoxic, and DNA-Protective Potential of 2,3-Substituted Quinazolinones: Structure-Activity Relationship Study.

The evaluation of antioxidant compounds that counteract the mutagenic effects caused by the direct action of reactive oxygen species on DNA molecule is of considerable interest. Therefore, a series of 2,3-substituted quinazolinone derivatives (Q1-Q8) were investigated by different assays, and the relationship between their biological properties and chemical structure was examined. Genotoxicity and the potential DNA-protective effects of Q1-Q8 were evaluated by comet assay and DNA topology assay. Antioxidant activity was examined by DPPH-radical-scavenging, reducing-power, and total antioxidant status (TAS) assays. The cytotoxic effect of compounds was assessed in human renal epithelial cells (TH-1) and renal carcinoma cells (Caki-1) by MTT assay. Analysis of the structure-activity relationship disclosed significant differences in the activity depending on the substitution pattern. Derivatives Q5-Q8, bearing electron-donating moieties, were the most potent members of this series. Compounds were not genotoxic and considerably decreased the levels of DNA lesions induced by oxidants (H2O2, Fe2+ ions). Furthermore, compounds exhibited higher cytotoxicity in Caki-1 compared to that in TH-1 cells. Substantial antioxidant effect and DNA-protectivity along with the absence of genotoxicity suggested that the studied quinazolinones might represent potential model structures for the development of pharmacologically active agents.

Evaluation of the genotoxic, DNA-protective and antioxidant profile of synthetic alkyl gallates and gallotannins using in vitro assays.

New gallotanins, methyl 2,3,4,6-tetra-O-galloyl-α-D-glucoside (G4Glc), methyl 2,3,4,6-tetra-O-galloyl-α-D-mannoside (G4Man), and methyl 2,3,4-tri-O-galloyl-α-L-rhamnoside (G3Rham), have been synthesized in order to study the protective effects of synthetic polyphenols that are structurally related with natural compounds. Apart from spectral analysis, examination of antioxidant ability and protective efficiency showed the differences among newly prepared compounds and commercial antioxidants - gallic acid (GA), methyl gallate (MG), and octyl gallate (OG) applying radical scavenging 1,1-diphenyl-2-picryl-hydrazyl (DPPH), reducing power and iron-chelating assays. The genotoxicity and DNA-protective potential of tested compounds on human peripheral blood mononuclear cells (PBMCs) were evaluated using the single-cell gel electrophoresis (comet assay) and DNA-topology assay. Experimental data revealed that gallotannins G3Rham, G4Man, and G4Glc possess significant radical scavenging/antioxidant activities and manifest very low genotoxic effect on human PBMCs. Moreover, tested compounds considerably reduce the level of DNA damage induced by hydrogen peroxide or Fe2+-ions. The results imply that new synthetic gallotannins can be considered as nontoxic agents for subsequent design of new antioxidants with potential biomedical applications.