Docking Studies, Cytotoxicity Evaluation and Interactions of Binuclear Copper(II) Complexes with S-Isoalkyl Derivatives of Thiosalicylic Acid with Some Relevant Biomolecules.

The numerous side effects of platinum based chemotherapy has led to the design of new therapeutics with platinum replaced by another transition metal. Here, we investigated the interactions of previously reported copper(II) complexes containing S-isoalkyl derivatives, the salicylic acid with guanosine-5'-monophosphate and calf thymus DNA (CT-DNA) and their antitumor effects, in a colon carcinoma model. All three copper(II) complexes exhibited an affinity for binding to CT-DNA, but there was no indication of intercalation or the displacement of ethidium bromide. Molecular docking studies revealed a significant affinity of the complexes for binding to the minor groove of B-form DNA, which coincided with DNA elongation, and a higher affinity for binding to Z-form DNA, supporting the hypothesis that the complex binding to CT-DNA induces a local transition from B-form to Z-form DNA. These complexes show a moderate, but selective cytotoxic effect toward colon cancer cells in vitro. Binuclear complex of copper(II) with S-isoamyl derivative of thiosalicylic acid showed the highest cytotoxic effect, arrested tumor cells in the G2/M phase of the cell cycle, and significantly reduced the expression of inflammatory molecules pro-IL-1ß, TNF-α, ICAM-1, and VCAM-1 in the tissue of primary heterotopic murine colon cancer, which was accompanied by a significantly reduced tumor growth and metastases in the lung and liver.

Synthesis, characterization, HSA binding, molecular docking, cytotoxicity study, and antimicrobial activity of new palladium(II) complexes with propylenediamine derivatives of phenylalanine.

The four new ligands, propylenediamine derivatives of phenylalanine (R2-S,S-pddbaˑ2HCl; L1-L4) and their palladium(II) complexes (C1-C4) were synthesized and characterized by elemental analysis, infrared, 1H and 13C NMR spectroscopy. The interactions of new palladium(II) complexes with human serum albumin (HSA) were studied by fluorescence spectroscopy. All investigated compounds can be transported to target cells by binding to HSA, but complex C4 interacts most strongly. Molecular docking simulations were applied to comprehend the binding of the complex to the molecular target of HSA. Obtained results are in good correlations with experimental data regarding binding affinity by HSA. In vitro cytotoxicity activities were investigated on four tumor cell lines (mouse mammary (4 T1) and colon (CT26), human mammary (MDA-MD-468) and colon (HCT116)) and mouse mesenchymal stem cells as non-tumor control cells. Cytotoxic capacity was determined by MTT test and according to obtained results ligand L4 stands out as the most active and selective compound and as a good candidate for future in vivo testing. Further examination of the ligand L4 and corresponding complex C4 led to the conclusion that both induced cell death mainly by apoptosis. Ligand L4 facilitated cycle arrest in G0/G1 phase and decreased proliferative capacity of tumor cells. In vitro antimicrobial activity for ligands and corresponding Pd(II) complexes was investigated against eleven microorganisms (eight strains of pathogenic bacteria and three yeast species) using microdilution method. The minimum inhibitory concentration and minimum microbicidal concentration were determined.

Synthesis, characterization, DNA interactions and biological activity of new palladium(II) complexes with some derivatives of 2-aminothiazoles.

Newly palladium(II) complexes (C1, C2) with derivatives of 2-aminothiazoles (L1 = 2-amino-6-methylbenzothiazole, L2 = 2-amino-6-chlorobenzothiazole), general formula [PdL2Cl2] were synthesized and characterized by elemental microanalyses, IR, NMR spectroscopy and X-ray spectroscopy in case of [Pd(L2)2Cl2]. The kinetic of the substitution reactions of complexes and the nucleophiles, such as guanosine-5'-monophosphate (5'-GMP), tripeptide glutathione (GSH) and amino acid L-methionine (L-Met), were studied by stopped-flow technique. The complex C2 was always more reactive, while the order of the reactivity of the nucleophiles, due to the associative mode of the reaction, was L-Met > GSH > 5'-GMP. In order to determine the type of interactions between palladium(II) complexes and calf thymus DNA (CT-DNA), we used electronic absorption spectroscopy, viscosity measurements, and fluorescence spectroscopic studies, while interactions with bovine serum albumin (BSA) were determined only with fluorescence spectroscopic studies. The observed results confirmed that both complexes bound to DNA by groove binding. The significantly strong interaction with BSA, especially for complex C2, was also observed. In vitro cytotoxic activity was evaluated against four tumor cell lines, 4 T1, CT26, MDA-MB-468, HCT116 and mesenchymal stem cells (mMSC). C1 complex showed higher cytotoxic activity against CT26 cell line. Flow cytometry analysis showed that C1 stimulated apoptosis of tumor cells via inhibition of expression of antiapoptotic Bcl-2 molecule and decelerated proliferation by decreasing Cyclin-D and increasing expression of P21. In vitro antimicrobial activity for ligands and corresponding palladium(II) complexes was investigated by microdilution method and minimum inhibitory concentration (MIC) and minimum microbicidal concentration (MMC) were determined. Tested compounds exhibited selective and moderate activity.

Antiproliferative, antimigratory, and prooxidative potential of novel platinum(IV) complexes and resveratrol on breast cancer (MDA-MB-231) and choriocarcinoma (JEG-3) cell lines.

Platinum(IV) complexes offer the potential to overcome cisplatin resistance of cancer cells, with possible improved selectivity. Resveratrol, a natural polyphenol with anticancer and antioxidant capacity, could limit the possible side effects of chemotherapeutics on healthy cells. This study investigates the effects of platinum(IV) complexes containing some esters of the ethylenediamine-N,N'-di-S,S-(2,2'-dibenzyl)acetate acid (H2 -S,S-eddba), and resveratrol on proliferation, migration, and redox balance of breast cancer (MDA-MB-231), choriocarcinoma (JEG-3), and human lung fibroblast (MRC-5) cell line. According to IC50 values, all complexes exhibited a significantly stronger antiproliferative effect on tested cell lines compared to cisplatin. Due to reduced adverse effects on MRC-5 cells, the complex containing ethyl-substituent (10 µM) was selected for further examination with resveratrol (25 µM) cotreatment. Resveratrol enhanced the survival of MRC-5 cells while diminished the viability of both used cancer cell lines when applied combined with selected complex. Furthermore, cotreatment of these two compounds decreased the migratory potential of tested cancer cell lines. The examined platinum(IV) complex was able to induce oxidative stress in all tested cell lines. Resveratrol proved to be efficient in protecting MRC-5 cells from complex-induced oxidative damage, while it significantly amplified antiproliferative, antimigratory, and prooxidative effects of platinum(IV) complex on both examined cancer cell lines. These findings may be valuable in elucidating the mechanism of action of platinum(IV) drugs, which should be further investigated.

Evaluation of Toxic Effects of Novel Platinum (IV) Complexes in Female Rat Liver: Potential Protective Role of Resveratrol.

The use of cisplatin in chemotherapy may provoke a deteriorating impact in many vital organs, suggesting the need for more selective derivatives and effective protective cotreatments. This study assesses the effects of three novel Pt(IV) complexes containing ethyl-, propyl- and butyl-esters of the ethylenediamine-N, N'-di-S, S- (2,2'-dibenzyl) acetic acid on liver injury markers, redox parameters, and cell morphology of female rat liver tissue in comparison to cisplatin. In addition, the study evaluates the possible protective effects of resveratrol as well. The rats were divided into ten groups and were administered intraperitoneally with a single dose of cisplatin (7.5 mg/kg) or Pt(IV) complexes (10 mg/kg) and/or resveratrol (25 mg/kg). All treatments caused changes in body weight, food intake, and liver/bw ratio. Acute treatment with novel complexes decreased the levels of TB and TP while elevated the activity of ALT, AST, GGT, ALP which subsequently indicated on the liver damage. All three complexes significantly reduced the levels of LPO, O2.-, NO2- and activity of CAT, while increasing the activity of SOD, GSH-Px, GR, GST, and level of GSH, implying that these compounds could provoke redox balance disruption in liver cells. Moreover, according to the histopathological observations, the novel Pt(IV) complexes exerted stronger hepatotoxicity than cisplatin. Possible protective effects of resveratrol were not detected and even combined with examined compounds it abolished the activity of the antioxidative system of the liver cells causing more intense toxicity. Further investigation is required to elucidate the effects of Pt-based drugs and resveratrol in the estradiol-rich environment of female rats as well their influence on male rats' tissues.

Synthesis, spectroscopic characterization (FT-IR, FT-Raman, and NMR), quantum chemical studies and molecular docking of 3-(1-(phenylamino)ethylidene)-chroman-2,4-dione.

The experimental and theoretical investigations of structure of the 3-(1-(phenylamino)ethylidene)-chroman-2,4-dione were performed. X-ray structure analysis and spectroscopic methods (FTIR and FT-Raman, 1H and 13C NMR), along with the density functional theory calculations (B3LYP functional with empirical dispersion corrections D3BJ in combination with the 6-311 + G(d,p) basis set), were used in order to characterize the molecular structure and spectroscopic behavior of the investigated coumarin derivative. Molecular docking analysis was carried out to identify the potency of inhibition of the title molecule against human's Ubiquinol-Cytochrome C Reductase Binding Protein (UQCRB) and Methylenetetrahydrofolate reductase (MTHFR). The inhibition activity was obtained for ten conformations of ligand inside the proteins.

Stereospecific ligands and their complexes. XXII. Synthesis and antitumor activity of palladium(II) complexes with some esters of (S,S)-ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid.

Four new ligands and their palladium(II) complexes of general formula R2-S,S-eddtyr (L1-L4) and [PdCl2(R2-S,S-eddtyr)] (C1-C4) (R=ethyl, n-propyl, n-butyl and n-pentyl; S,S-eddtyr·2HCl=ethylenediamine-N,N'-di-(2,2'-di(4-hydroxy-benzyl))-acetic acid dihydrochloride have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. Cytotoxicity for ligands and complexes on two different cell lines (human breast cancer, MDA-MB-231 and human lung cancer, A549 cell lines) and human chronic lymphocytic leukemia cells (CLL) was investigated using MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay.

Synthesis, characterization and cytotoxicity of a new palladium(II) complex with a coumarine-derived ligand.

The new coumarine derivative, 3-(1-(2-hydroxyethylamino)ethylidene)chroman-2,4--dione, and corresponding palladium(II) complex have been synthesized and characterized by microanalysis, infrared, (1)H and (13)C NMR spectroscopy. The proposed structure of the complex was confirmed on the basis of the X-ray structural study. The palladium(II) complex decreased viability of L929 mouse fibrosarcoma, U251 human glioma and B16 mouse melanoma cell lines in a dose dependent manner, while its ligand exhibited no significant cytotoxicity. The cytotoxic effect of the complex was comparable to that of cisplatin, and mediated by apoptosis associated with oxidative stress, mitochondrial depolarization and caspase activation. Therefore, our results indicate that newly synthesized palladium(II) complex might be a potential candidate for anticancer therapy.

Nickel(II) in chelate N2O2 environment. DFT approach and in-depth molecular orbital and configurational analysis.

The O-N-N-O-type tetradentate ligands H2S,S-eddp (H2S,S-eddp stands for S,S-ethylenediamine-N,N'-di-2-propionic acid) and H2edap (H2edap stands for ethylenediamine-N-acetic-N'-3-propionic acid) and the corresponding novel octahedral nickel(II) complexes have been prepared and characterized. N2O2 ligands coordinate to the nickel(II) ion via four donor atoms (two deprotonated carboxylate atoms and two amine nitrogens) affording octahedral geometry in the case of all investigated Ni(II) complexes. A six coordinate, octahedral geometry has been verified crystallographically for the s-cis-[Ni(S,S-eddp)(H2O)2] complex. Structural data correlating similarly chelated Ni(II) complexes have been used to carry out an extensive configuration analysis. Molecular mechanics and Density Functional Theory (DFT) have been used to model the most stable geometric isomer, yielding, at the same time, significant structural and spectroscopic (TDDFT) data. The results from density functional studies have been compared to X-ray data. Natural Bond Orbital (NBO) and Natural Energetic Decomposition Analysis (NEDA) have been done for the [Ni(edda-type)(H2O)(2-n)] and nH2O fragments. Molecular orbital analysis (MPA) is given as well. The infra-red and electronic absorption spectra of the complexes are discussed in comparison to the related complexes of known geometries.