Synthesis and Biological Screening of New 4-Hydroxycoumarin Derivatives and Their Palladium(II) Complexes.

Two newly synthesized 4-hydroxycoumarin bidentate ligands (L1 and L2) and their palladium(II) complexes (C1 and C2) were screened for their biological activities, in vitro and in vivo. Structures of new compounds were established based on elemental analysis, 1H NMR, 13C NMR, and IR spectroscopic techniques. The obtained compounds were tested for their antioxidative and cytotoxic activities and results pointed to selective antiradical activity of palladium(II) complexes towards •OH and -•OOH radicals and anti-ABTS (2,2'-Azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) cation radical) activity comparable to that of ascorbate. Results indicated the effect of C1 and C2 on the enzymatic activity of the antioxidative defense system. In vitro cytotoxicity assay performed on different carcinoma cell lines (HCT166, A375, and MIA PaCa-2), and one healthy fibroblast cell line (MRC-5) showed a cytotoxic effect of both C1 and C2, expressed as a decrease in carcinoma cells' viability, mostly by induction of apoptosis. In vivo toxicity tests performed on zebrafish embryos indicated different effects of C1 and C2, ranging from adverse developmental effect to no toxicity, depending on tested concentration. According to docking studies, both complexes (C1 and C2) showed better inhibitory activity in comparison to other palladium(II) complexes.

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.

The content of toxic and essential elements in trabecular and cortical femoral neck: a correlation with whole blood samples.

Pollution caused by heavy metals affects all forms of life. The aim of the study was to determine the content of toxic (Sr, Ni, Pb, V, Cd, U, Rb, As) and essential (Na, K, Ca, Mg, Zn, Cu, Se, Mn, Cr, Mo, Co) metals in the bone and whole blood samples, in regard to clinical means of long- and short-term exposure, respectively. For this purpose, the cortical and trabecular parts of femoral neck, as well as the blood samples, were collected to quantify bone-important metals by inductively coupled plasma (ICP)-based techniques. According to principal component analysis (PCA), the most influential metal discriminating blood samples was Cu, while all other quantified elements were present in higher amounts in the bones. Additionally, trabecular bones (TBs) could be characterized by higher content of Mo, Cr, V, Mn, Co, As, and Ni compared to cortical bones (CBs). Linear discrimination analysis (LDA) was successfully applied to distinguish trabecular bone from the cortical bone. Significant correlation between essential Ca and toxic Sr with other elements was found and discussed. This study provides novel data on the effects of metal pollutants on bone health hazards. The results obtained for investigating metals may serve as a baseline for further clinical investigations in the orthopedic fields.

Synthesis and Characterization of 3-(1-((3,4-Dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione as a Potential Antitumor Agent.

The newly synthesized coumarin derivative with dopamine, 3-(1-((3,4-dihydroxyphenethyl)amino)ethylidene)-chroman-2,4-dione, was completely structurally characterized by X-ray crystallography. It was shown that several types of hydrogen bonds are present, which additionally stabilize the structure. The compound was tested in vitro against different cell lines, healthy human keratinocyte HaCaT, cervical squamous cell carcinoma SiHa, breast carcinoma MCF7, and hepatocellular carcinoma HepG2. Compared to control, the new derivate showed a stronger effect on both healthy and carcinoma cell lines, with the most prominent effect on the breast carcinoma MCF7 cell line. The molecular docking study, obtained for ten different conformations of the new compound, showed its inhibitory nature against CDKS protein. Lower inhibition constant, relative to one of 4-OH-coumarine, proved stronger and more numerous interactions with CDKS protein. These interactions were carefully examined for both parent molecule and derivative and explained from a structural point of view.

Spectroscopic and theoretical investigation of the potential anti-tumor and anti-microbial agent, 3-(1-((2-hydroxyphenyl)amino)ethylidene)chroman-2,4-dione.

The coumarin-orthoaminophenol derivative was prepared under mild conditions. Based on crystallographic structure, IR and Raman, 1H and 13C NMR spectra the most applicable theoretical method was determined to be B3LYP-D3BJ. The stability and reactivity parameters were calculated, in the framework of NBO, QTAIM and Fukui functions, form the optimized structure. This reactivity was then probed in biological systems. The antimicrobial activity towards four bacteria and three fungi species was examined and activity was proven. In vitro cytotoxic effects, against human epithelial colorectal carcinoma HCT-116 and human healthy lung MRC-5 cell lines, of the investigated substance are also tested. Compound showed significant cytotoxic effects on HCT-116 cells, while on MRC-5 cells showed no cytotoxic effects. The effect of hydroxy group in ortho-position on the overall reactivity of molecule was examined through molecular docking with Glutathione-S-transferases.

Synthesis, characterization and biological evaluation of Pd(ii), Cu(ii), Re(i) and 99mTc(i) thiazole-based complexes.

A new thiazole-containing multidentate ligand 2-((2-phenylthiazol-4-yl)methylthio)ethanamine, L, was synthesized and used to prepare new complexes of the formula PdIILCl2 (Pd-L), CuIIL2Cl2 (Cu-L) and fac-[Re/99mTcI(CO)3(L)]+ (Re/99mTc-L). The ligand L and the metal complexes were characterized spectroscopically. Furthermore, the structures of Re-L and Cu-L were elucidated by X-ray crystallography. Ligand L acts as a bidentate (Nth, S) chelator in Pd-L, as a bidentate (N, S) chelator in Cu-L and as a tridentate (Nth, S, N) chelator in Re-L. The radiotracer 99mTc-L was synthesized in high yield and characterised by HPLC comparison with the Re-L analog. The synthesized compounds were evaluated for their anti-inflammatory and cytotoxic properties. The compounds exhibited low anti-inflammatory activity with Pd-L showing the highest activity among them. The cytotoxic activity of the ligand and the complexes against several human cancer cell lines (cervical adenocarcinoma HeLa, colorectal adenocarcinoma LS-174T, lung adenocarcinoma A549, breast adenocarcinoma MDA-MB-231 and normal human lung fibroblast cell line MRC-5) was examined using the MTT assay. The complex Cu-L exhibited the highest cytotoxicity and the complex Pd-L showed the best tumor selectivity. The changes in the cell cycle phase distribution were determined by flow cytometry and it was found that ligand L shows the highest apoptotic activity. The biodistribution studies of 99mTc-L in mice showed fast tissue clearance. Of all the thiazole-containing compounds, the palladium complex appears to be more promising for future efforts.

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.

In vitro antitumor activity, metal uptake and reactivity with ascorbic acid and BSA of some gold(III) complexes with N,N'-ethylenediamine bidentate ester ligands.

Four novel gold(III) complexes of general formulae [AuCl2{(S,S)-R2eddl}]PF6 (R2eddl=O,O'-dialkyl-(S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoate, R=n-Pr, n-Bu, n-Pe, i-Bu; 1-4, respectively), were synthesized and characterized by elemental analysis, UV/Vis, IR, and NMR spectroscopy, as well as high resolution mass spectrometry. Density functional theory calculations pointed out that (R,R)-N,N'-configuration diastereoisomers were energetically the most favorable. Duo to high cytotoxic activity complex 3 was chosen for stability study in DMSO, no decomposition occurs within 24h, and for the reaction with ascorbic acid in which was reduced immediately. Additionally, 3 interacts with bovine serum albumin (BSA) as proven by UV/Vis spectroscopy. In vitro antitumor activity was determined against human cervix adenocarcinoma (HeLa), human myelogenous leukemia (K562), and human melanoma (Fem-x) cancer cell lines, as well as against non-cancerous human embryonic lung fibroblast cells MRC-5. The highest activity was observed against K562 cells (IC50: 5.04-6.51µM). Selectivity indices showed that these complexes are less toxic than cisplatin. 3 had a similar viability kinetics on HeLa cells as cisplatin. Drug accumulation studies in HeLa cells showed that the total gold uptake increased much faster than that of cisplatin pointing out that 3 more efficiently enters the cells than cisplatin. Furthermore, morphological and cell cycle analysis reveal that gold(III) complexes induced apoptosis in time- and dose-dependent manner.

Low-dimensional compounds containing bioactive ligands. Part VI: Synthesis, structures, in vitro DNA binding, antimicrobial and anticancer properties of first row transition metal complexes with 5-chloro-quinolin-8-ol.

A series of new 3d metal complexes with 5-chloro-quinolin-8-ol (ClQ), [Mn(ClQ)2] (1), [Fe(ClQ)3] (2), [Co(ClQ)2(H2O)2] (3), [Ni(ClQ)2(H2O)2] (4), [Cu(ClQ)2] (5), [Zn(ClQ)2(H2O)2] (6), [Mn(ClQ)3]·DMF (7) and [Co(ClQ)3]·DMF·(EtOH)0.35 (8) (DMF=N,N-dimethylformamide), has been synthesized and characterized by elemental analysis, IR spectroscopy and TG-DTA thermal analysis. X-ray structure analysis of 7 and 8 revealed that these molecular complexes contain three chelate ClQ molecules coordinated to the central atoms in a deformed octahedral geometry and free space between the complex units is filled by solvated DMF and ethanol molecules. Antimicrobial activity of 1-6 was tested by determining the minimum inhibitory concentration and minimum microbicidal concentration against 12 strains of bacteria and 5 strains of fungi. The intensity of antimicrobial action varies depending on the group of microorganism and can be sorted: 1>ClQ>6>3/4>2>5. Complexes 1-6 exhibit high cytotoxic activity against MDA-MB, HCT-116 and A549 cancer cell lines. Among them, complex 2 is significantly more cytotoxic against MDA-MB cells than cisplatin at all tested concentrations and is not cytotoxic against control mesenchymal stem cells indicating that this complex seems to be a good candidate for future pharmacological evaluation. Interaction of 1-6 with DNA was investigated using UV-VIS spectroscopy, fluorescence spectroscopy and agarose gel electrophoresis. The binding studies indicate that 1-6 can interact with CT-DNA through intercalation; complex 2 has the highest binding affinity. Moreover, complexes 1-6 inhibit the catalytic activity of topoisomerase I.

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.

A novel caryophyllene type sesquiterpene lactone from Asparagus falcatus (Linn.); structure elucidation and anti-angiogenic activity on HUVECs.

In this study the novel caryophyllene type sesquiterpene lactone (aspfalcolide) has been isolated from the leaves of Asparagus falcatus (Linn.) and characterized by IR, 1D NMR, 2D NMR, EI-MS, HR-ESI-MS and X-ray single crystal diffraction analysis. The aspfalcolide crystallizes in the orthorhombic space group P2(1)2(1)2(1) with a = 6.37360(10), b = 7.6890(2), c = 27.3281(6) Å, α = ß = Î³ = 90(°) and Z = 4. One intermolecular O-H⋯O hydrogen bond enforces these natural molecules to form infinite chains through the crystal. Aspfalcolide was screened for its anti-angiogenic activity in human umbilical vein endothelial cells (HUVECs) and the result showed the remarkable inhibitory effect of aspfalcolide on the proliferation (IC(50) 1.82 µM), migration and tube formation of HUVECs.

Stereospecific ligands and their complexes. Part VII. Synthesis, characterization and in vitro antitumoral activity of platinum(II) complexes with O,O'-dialkyl esters of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid.

Platinum(II) complexes (1-4) with bidentate N,N'-ligands, O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)pentanoic acid were synthesized and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. DFT calculations were performed for the complexes and it was found that only one diastereoisomer could be formed. Cytotoxic activity of complexes 1-4 was determined against chronic lymphocytic leukemia cells (CLL) and compared to the activity of ligand precursors L1 · 2HCl-L4·2HCl and corresponding palladium(II) complexes, [PdCl(2)L] (L = L1-L4). The complexes were found to exhibit significantly higher antitumor activities than cisplatin on CLL cells. Cytotoxic effect of platinum(II) complexes on CLL cells was higher compared to corresponding palladium(II) complexes. In addition the mode of cell death induced by platinum(II) complexes was determined.

Palladium(II) complexes with R(2)edda derived ligands. Part IV. O,O'-dialkyl esters of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)-pentanoic acid dihydrochloride and their palladium(II) complexes: synthesis, characterization and in vitro antitumoral activity against chronic lymphocytic leukemia (CLL) cells.

Four novel bidentate N,N'-ligand precursors, including O,O'-dialkyl esters (alkyl = ethyl, n-propyl, n-butyl and n-pentyl), L1 x 2 HCl-L4 x 2 HCl, of (S,S)-ethylenediamine-N,N'-di-2-(4-methyl)-pentanoic acid dihydrochloride [(S,S)-H(4)eddl]Cl(2) and the corresponding palladium(II) complexes 1-4, were prepared and characterized by IR, (1)H NMR and (13)C NMR spectroscopy and elemental analysis. In vitro cytotoxicity of all compounds was determined against chronic lymphocytic leukemia cells (CLL). The compounds were found to exhibit higher antitumoral activity than cisplatin. The most active compound 2, [PdCl(2){(S,S)-nPr(2)eddl}], was found to be 13.6 times more active than cisplatin on CLL cells.

Synthesis and in vitro antitumoral activity of novel O,O'-di-2-alkyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate ligands and corresponding platinum(II/IV) complexes.

Syntheses of two novel ligand precursors O,O'-diisopropyl- (1a) and O,O'-diisobutyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate dihydrochloride monohydrate (1b) and the corresponding dichloroplatinum(II) (2a and 2b) and tetrachloroplatinum(IV) complexes (3a and 3b) are described here. The substances were characterized by IR, (1)H and (13)C spectroscopy and elemental analysis. Crystal structures were determined for 1a and the corresponding platinum(IV) complex, 3a. In vitro antiproliferative activity was determined against tumor cell lines: human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, rested and stimulated normal immunocompetent cells (human peripheral blood mononuclear PBMC cells) using KBR test (Kenacid Blue Dye binding test). The IC(50)(microM) values for the most active compound 3a were: 30.48+/-2.54; 12.26+/-2.60; 13.68+/-3.22; 80.18+/-24.07 and 71.30+/-21.70, respectively.

Synthesis, structure, and hydrolytic reaction of trans-dichlorobis(diethanolamine-N)palladium(II) with N-acetylated L-histidylglycine dipeptide.

The reaction of PdCl2, or K2PdCl4, with diethanolamine (DEA), in the molar ratio 1:2, affords the trans-[PdCl2(DEA)2] complex. X-ray structure analysis of this complex confirmed the formation of the trans-isomer. The complex crystallizes in the space group P42bc. The central Pd(II) ion is coordinated in an almost ideal square-planar fashion with a small deformation of the Cl-Pd-Cl angle (175.6(7) degrees) due to N-H...Cl hydrogen bonding. The N-H group participates in a bifurcated interaction with the two symmetry related Cl- anions. The hydroxyl groups of the diethanolamine ligand form very strong hydrogen bonds between the complex units, thus leading to infinite zigzag (O-H...O-H...O-H..) chains in the crystal packing. The complex units are further connected by weaker intermolecular hydrogen bonds of the N-H...Cl type in a way to form layers parallel to the crystallographic (001) plane. The reaction between the trans-[PdCl2(DEA)2] or trans-[Pd(H2O)2(DEA)2]2+ complex and MeCOHis-Gly dipeptide at 1.5 < pH < 2.0 and at 25 degrees C leads to the regioselective cleavage of the amide bond involving the carboxylic group of the histidine. The cleavage of the substrate was fast and went almost to completion within less than one hour.