DNA binding, topoisomerase inhibition and cytotoxicity of palladium(II) complexes with 1,10-phenanthroline and thioureas (original) (raw)
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International Journal of Molecular Sciences
Ovarian cancer is the most lethal gynecological malignancy, often because of the frequent insurgence of chemoresistance to the drugs currently used. Thus, new therapeutical agents are needed. We tested the toxicity of 16 new DNA-intercalating agents to cisplatin (cDDP)-sensitive human ovarian carcinoma cell lines and their resistant counterparts. The compounds were the complexes of Pt(II) or Pd(II) with bipyridyl (bipy) and phenanthrolyl (phen) and with four different thiourea ancillary ligands. Within each of the four series of complexes characterized by the same thiourea ligand, the Pd(phen) drugs invariably showed the highest anti-proliferative efficacy. This paralleled both a higher intracellular drug accumulation and a more efficient DNA intercalation than all the other metal-bidentate ligand combinations. The consequent inhibition of topoisomerase II activity led to the greatest inhibition of DNA metabolism, evidenced by the inhibition of the expression of the folate cycle enz...
Inorganica Chimica Acta, 2021
Complexes [Pd(bipy)(mtzt) 2 ] (1) and [Pd(5,6-dmphen)(mtzt) 2 ] (2) (where Hmtzt, bipy and 5,6-dmphen are 1methyl-1H-1,2,3,4-tetrazole-5-thiol, 2,2′-bipyridine and 5,6-dimethyl-1,10-phenanthroline, respectively) were synthesized by the reaction of a mixture of Hmtzt and 2,2′-bipyridine (1) or 5,6-dimethyl-1,10-phenanthroline (2) with Pd(II) chloride. Complexes 1 and 2 were fully characterized by elemental analysis, 1 H NMR, IR, UV-Vis, luminescence spectroscopy as well as single-crystal X-ray diffraction method. According to single-crystal X-ray diffraction, central Pd(II) ions in 1 and 2 have a slightly distorted square-planar geometry, involving the S atoms from two mptrz − ligands and two nitrogen atoms from bipy (complex 1) and 5,6-dmphen (complex 2) ligands (τ 4 = 0.09 for 1 and 0.07 for 2). Additionally, some well-known non-covalent intermolecular interactions such as hydrogen bonding (complexes 1 and 2), π-π (complexes 1 and 2), and ring-metal interactions (complex 2) have also been involved in these complexes. These kinds of interactions have been observed to be responsible for the formation of the 3D supramolecular structure. The luminescence properties of the free ligand, as well as the complexes 1 and 2, were investigated in solution. The interaction of the complexes with DNA was investigated by UV-Vis absorption spectra. The results indicate that complexes bind to DNA and the intrinsic binding constant (K b) of complexes 1 and 2 were about 2.19 × 10 5 and 1.51 × 10 5 M −1 , respectively. Gel electrophoresis assay demonstrates the ability of the complexes to bind the plasmid DNA. The anti-tumor properties of Pd(II) complexes were evaluated as in vitro anti-proliferative activity by MTT assay in human breast cancer cell lines (MCF-7, SKBR-3, and MDA-MB-231). It suggests that complex 2 might dedicate important anti-tumor properties and 5,6-dmphen ligand has an important effect on cytotoxicity, so complex 2 shows IC 50 value in μM range as effective as cisplatin.
Journal of Organometallic Chemistry, 2017
Novel organometallic palladium(II) complexes [Pd 2 {(C,N)-C 12 H 8 NH 2)} 2 (µ-dppf)Cl 2 ] (2) [Pd 2 {(C,N)-C 12 H 8 NH 2)} 2 (µ-dpp)Cl 2 ] (3) [1,1-bis(diphenylphosphine)-ferrocene (dppf), 1,3-Bis(4-pyridyl)propane (bpp)] have been synthesized, fully characterized by elemental analysis, multi-nuclear (1 H, 31 P{1H}, 13 C{1H}) NMR and IR spectroscopic techniquesand their biological activities such as anti-tumoralactivity and DNA-protein interactions have been investigated. The crystal structure of (2), established by X-ray diffraction, shows that the dppf ligand is bound to the two palladium atoms in bridgedform. The interaction of the complexes with calf thymus DNA (CT-DNA) has been explored by UV-Vis spectroscopy, emission titration and thermal denaturation (T m) methods, which have revealed that these complexes interact with DNA through intercalation mode. Competitive studies with methylene blue (MB) have shown the ability of the complexes to displace the DNAbound MB, suggesting a competition with MB. Furthermore, the microenvironment and the secondary structure of BSA are changed in the presence of the complexes. Competitive binding using Warfarin, Digoxin and site markers, which have definite binding sites, demonstrated that the complexes bind to site I on BSA. Notably, the complexes exhibit significant in vitro selective cytotoxicity against two human cancer cell lines (JURKAT and SKOV3) with IC 50 values varying from 2.3 to 6.7 μM. This indicates that they are more active than cisplatin and showing low cytotoxic activity on normal cells. Finally, molecular modelling studies have been conducted to determine the binding site of the DNA and BSA with the complexes.
Journal of Inorganic Biochemistry, 2008
Six bipyridyl complexes of platinum(II) with thiourea, with different substituents on thiourea moiety [Pt(bipy)(R,R 0 NCSNR 00 ,R 000 ) 2 ]Cl 2 (bipy = 2,2 0 -bipyridine: R = R 0 = R 00 = R 000 = H; R = Me, R 0 = R 00 = R 000 = H; R = n-Bu, R 0 = R 00 = R 000 = H; R = Et, R 0 = H, R 00 = Et, R 000 = H; R = p-tolyl, R 0 = R 00 = R 000 = H; R = phenyl, R 0 = H, R 00 = phenyl, R 000 = H), rationally designed to intercalate into DNA, have been tested against a cisplatin (cDDP)-sensitive human ovarian carcinoma cell line (2008) and its -resistant variant (C13 * ). We show here that the anti-proliferative efficacy of these drugs was dependent on molecular structure, since it increased with ancillary ligand bulkiness and hydrophobicity of substituents on thiourea moiety. In particular, the presence of two phenyl groups on thiourea moiety confers an outstanding cytotoxicity. The increasing cell growth inhibition along the series of complexes partially paralleled with drug accumulation, particularly in resistant cells, but not with drug intercalation into DNA since all compounds exerted comparable ethidium bromide displacement ability. The cDDP-resistant phenotype seems, at least in part, to be involved in the action of these compounds, since the level of cross-resistance established for most complexes appeared to be in agreement with the observed impairment of drug accumulation in the resistant subline. These findings indicate that resistance to alkylating agents such as cDDP confers low level of cross-resistance to this class of DNA intercalators, which, however, depending on substituents on thiourea moiety may present remarkable cell growth inhibition even of resistant cells.
Two newly-created water-soluble complexes of palladium(II)/platinum(II)-dithiocarbamate, [Pd/Pt(phen)(pyr-dtc)]NO 3 (phen = 1,10-phenanthroline and pyr-dtc = pyrrolidinedithiocarbamate) were synthesized. Also, their chemical characteristics are reported in the current research paper. In these complexes, the dithiocarbamato ligand coordinates to Pt(II) or Pd(II) center with two sulfur atoms as bidentate. They were examined for their cytotoxic properties against chronic myelocytic leukemia K562 cell lines. These complexes showed 50% cytotoxic concentration (Cc 50) values much lower than those of cisplatin. The interactions of the two complexes with calf thymus DNA (CT-DNA) were investigated using UV-vis absorption, fluorescence emission, ethidium bromide displacement and gel filtration techniques. The results suggest that these complexes cooperatively bind with and denature the DNA at low concentrations and interact with CT-DNA in the intercalation mode. Gel filtration studies indicat...
Journal of Photochemistry and Photobiology B: Biology, 2012
The new heterobimetallic Cu II-Sn IV 2 =Ni II-Sn IV 2 complexes 1 and 2 bearing bioactive pharmacophore ligand scaffold; 1,10-phenanthroline and ethylenediamine were synthesized and characterized by spectroscopic (IR, UV-vis, NMR, ESI-MS) and analytical methods. The in vitro DNA binding studies of 1 and 2 with CT-DNA were carried out by employing various biophysical methods which reveal strong electrostatic binding via phosphate backbone of DNA helix, in addition to partial intercalation in the minor groove and stabilized by intramolecular hydrogen bonding. To gain further insight into the molecular recognition at the target site, UV-vis titrations of 1 with 5 0-GMP was carried out and validated by 1 H and 31 P NMR. Complex 1 cleaved pBR322 DNA via oxidative pathway and exhibited high inhibition activity against Topo-I at 20 lM. Furthermore, the cytotoxicity of 1 was examined on a panel of human tumor cell lines of different histological origins showing promising antitumor activity.
Polyhedron, 2013
A new series of complexes of general formulae [PdX2(tmdmPz)] {X = Cl (1), Br (2), I (3), SCN (4); tmdmPz = N0-methyl-3,5-dimethyl-1-thiocarbamoylpyrazole} have been synthesized and characterized by elemental analysis, molar conductivities, IR, 1H and 13C{1H} NMR spectroscopy. In these complexes, the tmdmPz coordinates to Pd(II) center as a neutral N,S-chelating ligand. The geometries of the complexes have been optimized with the DFT method. Cytotoxicity evaluation against LM3 (mammary adenocarcinoma) and LP07 (lung adenocarcinoma) cell lines indicated that complexes 1–4 were more active than cisplatin. The binding of the complexes with a purine base (guanosine) was investigated by 1H NMR and mass spectrometry, showing that the coordination of guanosine occurs through N7. Electrophoretic DNA migration studies showed that all of them modify the DNA tertiary structure.
New dimeric and supramolecular mixed ligand Palladium(II) dithiocarbamates as potent DNA binders
Polyhedron, 2012
Five Pd(II)-based potential potent metallopharmaceuticals (1-5) of the general formula [(DT)Pd(PR 3)Cl], where DT = dibutyldithiocarbamate (1,2), dipropyldithiocarbamate (3), bis(2-methoxyethyl)-dithiocarbamate (4), dimethyldithiocarbamate (5); PR 3 = triphenylphosphine (1), diphenyl-p-tolylphosphine (2), diphenyl-t-butylphosphine (3), diphenyl-2-methoxyphenylphosphine (4), p-cholorodiphenylphosphine (5), have been synthesized and characterized using FT-IR, Raman, and multinuclear-NMR spectroscopy. The X-ray single crystal analysis (1 and 2) reveals the Pd(II) moiety is in a distorted square-planar arrangement with two positions being occupied by the bidentate dithiocarbamate ligand, while the other two positions are occupied by a phosphine ligand and a chloro group. The packing diagrams confirmed that the intermolecular ClÁ Á ÁH interactions are not only the main cause of deviation from an ideal square planar geometry, but are also responsible for the Pd-S bond lengths variation. The DNA binding ability of the complexes was examined by cyclic voltammetry (CV). The cyclic voltammograms of the synthesized metallopharmaceuticals followed irreversible electrochemical behavior, which indicate the high reactivity of the reduced form of complexes. The results obtained from CV evidenced the catalytic role of DNA in enhancing the electron transfer processes of the complexes. The DNA binding studies are expected to provide useful insights about the unexplored mechanism by which anticancer drugs exert their biochemical action.