This paper presents the synthesis and structural characterization of a series of new ruthenium(II) complexes 1-7, with the general formula
-RuL
(
-
)ClCl, where L is 2,2':6',2''-terpyridine (tpy) or ...4'-(4-chlorophenyl)-2,2':6',2''-terpyridine (Cl-Ph-tpy) and
-
is
-benzoquinonediimine (
-bqdi), 2,3-naphthoquinonediimine (nqdi), 4,4'-dimethyl-2,2'-bipyridine (dmbpy) or 2,2'-bipyridine-4,4'-dicarboxylic acid (dcbpy). The kinetic results showed that the ligand substitution reactions of new Ru(II)-polypyridyl complexes with biomolecules were affected by different substituents and the aromaticity of meridional tridentate and bidentate spectator ligands as well as by the nature of the entering nucleophile. The reactivity of the complexes increases in the order: dmbpy < dcbipy < nqdi <
-bqdi. In addition, quantum chemical calculations were performed to support the interpretation and discussion of the experimental data. Furthermore, combining ethidium bromide (EB) and Hoechst 33258 (2-(4-hydroxyphenyl)-5-5-(4-methylpiperazine-1-yl)benzimidazo-2-yl-benzimidazole) fluorescence assay results implied that 1-7 might interact with calf thymus DNA through partial intercalation and/or minor groove binding. The human serum albumin (HAS)-fluorescence binding studies involving the site markers, eosin Y, as a marker for site I of subdomain IIA, and ibuprofen, as a marker for site II of subdomain IIIA, showed that Ru(II) compounds bind to both sites with moderately strong affinity (
= 10
-10
M
). Moreover, these DNA/HSA experimental results were confirmed by molecular docking. Complexes 2, 5 and 6 exerted good to strong and highly selective cytotoxic activity against breast adenocarcinoma (MDA-MB 231), colorectal carcinoma (HCT116) and cervix adenocarcinoma (HeLa). Depending on their structure and cell line, the complexes acted differently in terms of their influence on autophagy, the cell cycle and the engaged apoptotic pathway.
Four new complexes Pd(H2LtBu)ClCl (Pd1), Pt(H2LtBu)ClCl (Pt1), Pd(Me2LtBu)ClCl (Pd2) and Pt(Me2LtBu)ClCl (Pt2) (where H2LtBu = 2,6-bis(5-(tert-butyl)-1H-pyrazol-3-yl)pyridine and ...Me2LtBu = 2,6-bis(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)pyridine) were synthesized and characterized by elemental microanalysis, IR, 1H NMR and ESI-MS methods. The reactivity of complexes towards thiourea (Tu), l-methionine (l-Met), l-cysteine (l-Cys) and guanosine-5′-monophosphate (5′-GMP) was investigated. The obtained order was established as follows: Tu > l-Cys > l-Met > 5′-GMP. Complexes Pd1 and Pt1, that contain H2LtBu as chelator, showed higher reactivity towards biomolecules than those with Me2LtBu. The interaction of complexes with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) was studied by UV–Vis and fluorescence spectroscopy. The results have shown that complexes can bind to DNA exhibiting high binding constants (Kb = 104 M−1). Obtained results during the examination of competitive reaction with ethidium bromide (EB) showed that complexes can replace EB-bound DNA. High values of binding constants indicate good binding affinity of complexes towards BSA. We evaluated the stability differences between complexes based on terpy as well as H2LtBu/Me2LtBu by DFT calculations (B3LYP(CPCM)/LANL2DZp), showing that both tridentate ligand systems lead to complexes of similar stability. The results of biological testing showed that all complexes exert moderate to high selective cytotoxicity, inducing apoptosis and autophagy in HeLa and PANC-1 tumor cell lines. Pd1 exhibited the strongest cytotoxic effect. Finally, cell cycle analysis showed that in HeLa cells Pd1, Pd2 and Pt1 induced accumulation of cells in S phase, whereas in PANC-1 cells Pd2 and Pt1 induced G2/M cycle arrest and Pd1 induced G0/G1 arrest.
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•Synthesis and characterization of four new platinum(II) and palladium(II) complexes.•Substitution reactions with biological relevant nucleophiles were examined.•Interactions with calf thymus DNA (CT-DNA) and bovine serum albumin (BSA) were studied.•Stability difference of complexes with terpy and H2LtBu/Me2LtBu ligands are calculated.•Cytotoxic activity and impact on cell cycle were established on different cell lines.
•Anticancer evaluation and investigation of mechanism of action of some acylpyruvates.•The majority of acylpyruvates showed excellent cytotoxic activity against malignant cell lines in low IC50 ...values.•Acylpyruvates exhibited very good selectivity which, one of the crucial factors for a new antitumor drug candidate.•Protein binding study showed that these compounds could be adequately distributed and transported through the cells.
With the idea of finding a new antitumor drug with better or similar to one already used in clinical practice today, we tested a small series of acylpyruvate on a cisplatin-resistant MDA-MB-231 tumor cell line. All but one of the compounds in the series showed better cytotoxicity than cisplatin. In addition, compounds that showed good cytotoxicity on the MDA-MB-231 cell line were also tested on the normal MRC-5 cell line to determine its selectivity. All tested compounds showed better selectivity in the tested cell line than cisplatin. Good selectivity is one of the crucial factors for a new antitumor drug candidate. By examining the interactions with DNA, we concluded that our compounds interact with the DNA molecule through intercalation. On the other hand, by examining the binding mode of acylpyruvate to a transport protein, it was found that these compounds interact with the tested protein, indicating that the tested compound can be transported and adequately distributed to cells. A molecular docking study was performed to examine in more detail the sites and mode of binding to DNA and serum albumin molecules. In conclusion, all results indicate the great potential for the prospective application of these compounds in clinical practice in the future.
Clinical manifestations of SARS-CoV-2 infection range from mild to critically severe. The aim of the study was to highlight the immunological events associated with the severity of SARS-CoV-2 ...infection, with an emphasis on cells of innate immunity. Thirty COVID-19 patients with mild/moderate symptoms and 27 patients with severe/critically severe symptoms were recruited from the Clinical Center of Kragujevac during April 2020. Flow cytometric analysis was performed to reveal phenotypic and functional alterations of peripheral blood cells and to correlate them with the severity of the disease. In severe cases, the number of T and B lymphocytes, dendritic cells, NK cells, and HLA-DR-expressing cells was drastically decreased. In the monocyte population proportion between certain subsets was disturbed and cells coexpressing markers of M1 and M2 monocytes were found in intermediate and non-classical subsets. In mild cases decline in lymphocyte number was less pronounced and innate immunity was preserved as indicated by an increased number of myeloid and activated dendritic cells, NK cells that expressed activation marker at the same level as in control and by low expression of M2 marker in monocyte population. In patients with severe disease, both innate and adoptive immunity are devastated, while in patients with mild symptoms decline in lymphocyte number is lesser, and the innate immunity is preserved.
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•Synthesis and cytotoxic properties of novel 3-hydroxy-3-pyrrolin-2-ones bearing thenoyl fragment.•Compounds D10, D13, D14, and D15 showed highest cytotoxicity against malignant ...cells.•Mechanisms of cytotoxic activity suggested that D13, D15, and D10 in HeLa cells induce apoptosis that is associated with S phase arrest.•D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation.
In order to make a progress in discovering a new agents for chemotherapy with improved properties and bearing in mind the fact that substituted 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically active compounds, series of novel 1,5-diaryl-4-(2-thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones were synthesized and characterized by spectral (UV–Vis, IR, NMR, ESI-MS), X-ray and elemental analysis. All compounds were examined for their cytotoxic effect on human cancer cell lines HeLa and MDA-MB 231 and normal fibroblasts (MRC-5). Four compounds, 3-hydroxy-1-(p-tolyl)-4-(2-thienylcarbonyl)-5-(4-chlorophenyl)-2,5-dihydro-1H-pyrrol-2-one (D10), 3-hydroxy-1-(3-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D13), 3-hydroxy-1-(4-nitrophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D14), and 3-hydroxy-1-(4-chlorophenyl)-4-(2-thienylcarbonyl)-5-(4-(benzyloxy)phenyl)-2,5-dihydro-1H-pyrrol-2-one (D15), that showed the highest cytotoxicity against malignant cells and the best selectivity towards normal cells were selected for further experiments. Results obtained by investigating mechanisms of cytotoxic activity suggest that selected 3-hydroxy-3-pyrrolin-2-one derivatives in HeLa cells induce apoptosis that is associated with S phase arrest (D13, D15, and D10) or unrelated to cell cycle distribution (D14). Additionally, to better understand their suitability for potential use as anticancer medicaments we studied the interactions between biomacromolecules (DNA or BSA) and D13 and D15. The results indicated that D13 and D15 have great affinity to displace EB from the EB-DNA complex through intercalation Ksv = (3.7 ± 0.1) and (3.4 ± 0.1) × 103 M−1, respectively, an intercalative mode also confirmed through viscosity measurements. Ka values, obtained as result of fluorescence titration of BSA with D13 and D15 Ka = (4.2 ± 0.2) and (2.6 ± 0.2) × 105 M, respectively, support the fact that a significant amount of the tested compounds could be transported and distributed through the cells. In addition, by DNA and BSA molecular docking study for D13, D14 and D15 is determined and predicted the binding mode and the interaction region.
In order to make progress in discovering the new agents for cancer treatment with improved properties and considering the fact that 3-hydroxy-3-pyrrolin-2-ones belong to a class of biologically ...active compounds, we tested series of eleven novels 1,5-diaryl-4-(2- thienylcarbonyl)-3-hydroxy-3-pyrrolin-2-ones for their antitumor potential.
All novel compounds were characterized by spectral (IR, NMR, MS) and elemental analysis. All novel 3-hydroxy-3-pyrrolin-2-ones were screened for their cytotoxic activity on two cancer cell lines, SW480 and MDA-MB 231, and non-transformed fibroblasts (MRC-5).
Compounds B8, B9, and B10 showed high cytotoxicity on SW480 cells together with good selectivity towards MRC-5 cells. It is important to empathize that the degree of selectivity of B8 and B10 was high (SI = 5.54 and 12.09, respectively). Besides, we explored the mechanisms of cytotoxicity of novel derivatives, B8, B9, and B10. The assay showed that tested derivatives induce an apoptotic type of cell death in SW480 cells, with a minor percent of necrotic cells. Additionally, to better understand the suitability of the compounds for potential use as anticancer medicaments, we studied their interactions with biomacromolecules (DNA or BSA). The results indicated that the tested compounds have a great affinity to displace EB from the EB-DNA complex through intercalation. Also, DNA and BSA molecular docking study was performed to predict the binding mode and the interaction region of the compounds.
Achieved results indicate that our compounds have the potential to become candidates for use as medicaments.
L. is a well-known aromatic plant used in traditional medicine and the food and cosmetics industry. The aim of this study is to assess the antioxidant, genotoxic, antigenotoxic and cytotoxic ...properties of characterized hyssop essential oils and methanol extracts. Chemical composition was analyzed by gas chromatography - mass spectrometry (GC-MS) and liquid chromatography with diode array detection and mass spectrometry (LC-DAD-MS), respectively. Antioxidant activity was examined by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferric reducing/antioxidant power (FRAP) tests; genotoxic and antigenotoxic activity were examined by the comet assay, while cytotoxicity was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide dye (MTT) test against tumor cell lines (SW480, MDA-MB 231, HeLa) and non-transformed human lung fibroblast cell lines (MRC-5). The essential oils were rich in monoterpene hydrocarbons (e.g., limonene; 7.99-23.81%), oxygenated monoterpenes (1,8-cineole; 38.19-67.1%) and phenylpropanoids (methyl eugenol; 0.00-28.33%). In methanol extracts, the most abundant phenolics were chlorogenic and rosmarinic acid (23.35-33.46 and 3.53-17.98 mg/g, respectively). Methanol extracts expressed moderate to weak antioxidant activity (DPPH IC
= 56.04-199.89 µg/mL, FRAP = 0.667-0.959 mmol Fe
/g). Hyssop preparations significantly reduced DNA damage in human whole blood cells, induced by pretreatment with hydrogen peroxide. Methanol extracts exhibited selective and potent dose- and time-dependent activity against the HeLa cell line. Results of the current study demonstrated notable
.
medicinal potential, which calls for further investigation.
The aim of this study was to improve the mechanical properties and to optimize antimicrobial activity of hydroxyapatite (HAP) by simultaneous doping with Mg and Cu ions in order to obtain material ...that would be able to assist in the bone/tooth healing process, prevent post-implementation infections and provide satisfying values of hardness and fracture toughness for biomedical application. Ion doping was done during the hydrothermal synthesis of HAP powders, whereby the content of Mg ions in the starting solution was varied between 1-20 mol. % with regard to Ca ions, while the amount of Cu ions was kept constant at 0.4 mol. %. The green compacts were sintered for 2 h at temperatures ranging 750–1200 °C depending on the Mg content, chosen in agreement with dilatometry results. Presence of Mg ions was found to favour transition from HAP to β−tricalcium phosphate phase (β−TCP), which enabled formation of biphasic HAP/β−TCP and pure β−TCP phase at 160 °C during hydrothermal synthesis. In vitro investigation of antimicrobial activity against Escherichia coli, Staphylococcus aureus and Enterococcus faecalis showed satisfactory antimicrobial activity. MTT assay performed on MRC-5 and L929 cell lines showed excellent cytocompatibility and cell proliferation. Maximum hardness by Vickers and fracture toughness values, 4.96 GPa and 1.75 MPa m1/2 respectively, were obtained upon addition of 5 mol. % Mg, as a consequence of the lowest grain size and porosity, as well as the highest densification rate. This is, to the best of our knowledge, the highest fracture toughness for HAP or β-TCP ceramics reported thus far.
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