Maureen Walsh

Copper(II) complexes of coumarin-derived Schiff bases and their anti-Candida activity.

The condensation of 7-amino-4-methyl-coumarin (1) with a number of substituted salicylaldehydes yielded a series of Schiff bases (2a-2k) in good yields. Subsequent reaction of these ligands with copper(II) acetate yielded Cu(II) complexes (3a-3k) and some were characterised using X-ray crystallography. All of the free ligands and their metal complexes were tested for their anti-Candida activity. A number of the ligands and complexes exhibited anti-Candida activity comparable to that of the commercially available antifungal drugs, ketoconazole and Amphotericin B.

Role of cell cycle events and apoptosis in mediating the anti-cancer activity of a silver(I) complex of 4-hydroxy-3-nitro-coumarin-bis(phenanthroline) in human malignant cancer cells

The central objective of the current study was to investigate the potential in vitro anti-proliferative effect of 4-hydroxy-3-nitro-coumarin (hncH), and the mixed-ligand silver (I) complex of 4-oxy-3-nitro-coumarin-bis(phenanthroline), [Ag(hnc)(phen)(2)] using four human-derived model cell lines. In addition, selected mechanistic studies were carried out using the most sensitive of the four cell lines. Results obtained show that the complex could decrease the proliferation of all four cell lines including neoplastic renal and hepatic, namely A-498 and HepG(2) cells, respectively, along with two non-neoplastic renal and hepatic cell lines, HK-2 and Chang, respectively. Furthermore, non-neoplastic hepatic cells (Chang) appeared to be less sensitive to the effect of the complex, but this effect was not replicated in the non-neoplastic renal (HK-2) cells. Based on IC(50) values [Ag(hnc)(phen)(2)] was shown to be almost four times more potent than cisplatin, using HepG(2) cells. In addition, the observed anti-proliferative effect was shown to be both dose- and time-dependent. Furthermore, the complex was shown to decrease DNA synthesis, but did not intercalate with it. Moreover, there was no evidence that P-glycoprotein-mediated multi-drug resistance was likely to decrease anti-proliferative activity. Cytological stains, analysis of genomic DNA, and biochemical assays [caspase-3 and -9 and cleaved poly(ADP-ribose)-polymerase protein] showed that cell death appeared to result from apoptosis, with the possibility of secondary necrosis. Additionally, flow cytometric analysis showed that the complex functioned through an alteration in cell cycle progression. Taken together, [Ag(hnc)(phen)(2)] has been shown to be a more potent anti-proliferative agent than cisplatin, capable of altering key biochemical events leading to cell death. Additional mechanistic studies are underway to probe more fully its mechanism of action.

Anti-cancer activity and mutagenic potential of novel copper(II) quinolinone Schiff base complexes in hepatocarcinoma cells

This study determined the cytotoxic, cyto-selective and mutagenic potential of novel quinolinone Schiff base ligands and their corresponding copper(II) complexes in human-derived hepatic carcinoma cells (Hep-G2) and non-malignant human-derived hepatic cells (Chang). Results indicated that complexation of quinolinone Schiff bases with copper served to significantly enhance cytotoxicity. Here, the complex of (7E)-7-(3-ethoxy-2-hydroxybenzylideamino)-4-methylquinolin-2(1H)-one (TV117-FM) exhibited the lowest IC(50) value (17.9 μM) following 96 h continuous exposure, which was comparable to cisplatin (15.0 μM). However, results revealed that TV117-FM lacked cytoselectivity over non-malignant cells. Additionally, the complex was minimally effluxed from cells via Pglycoprotein (P-gp) and was shown to be non-mutagenic in the Standard Ames test. Furthermore, BrdU incorporation assays showed that it was capable of inhibiting DNA synthesis in a concentrationand time-dependent manner. However, inhibition was not as a consequence of DNA intercalation, as illustrated in electrophoretic mobility shift assays. Interestingly, it was shown that the ligand was capable of inhibiting the action of topoisomerase II, but this was lost following complexation. This indicated that the mechanism of action of the novel copper(II) complex was different from that of the parent ligand and suggests that TV117-FM may have a therapeutic role to play in the treatment of hepatocellular carcinoma. Studies are currently underway to elucidate the exact in vitro mechanism of action of this novel, metal-based anti-cancer agent.

Biological activity and coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands

The coordination modes of copper(II) complexes of Schiff base-derived coumarin ligands, which had previously shown good anti-Candida activity, were investigated by pH-potentiometric and UV-Vis spectroscopic methods. These studies confirmed the coordination mode of the ligands to be through the N of the imine and deprotonated phenol of the coumarin-derived ligand in solution. In addition, the more active complexes and their corresponding ligands were investigated in the presence of copper(II) in liquid and frozen solution by ESR spectroscopic methods. A series of secondary amine derivatives of the Schiff base ligands, were isolated with good solubility characteristics but showed little anti-Candida activity. However, cytotoxicity studies of the secondary amines, together with the copper complexes and their corresponding ligands, against human colon cancer and human breast cancer cells identified the chemotherapeutic potential of these new ligands.

Interaction of anticancer reduced Schiff base coumarin derivatives with human serum albumin investigated by fluorescence quenching and molecular modeling

The specific binding of five reduced Schiff base derived 7-amino-coumarin compounds with antitumor activity to human serum albumin, the principal binding protein of blood, was studied by fluorescence spectroscopy. Their conditional binding constants were computed and the reversible binding at the Sudlows site I was found to be strong (KD∼0.03-2.09 μM). Based on the data albumin can provide a depot for the compounds and is responsible for their biodistribution and transport processes. The experimental data is complemented by protein-ligand docking calculations for two representatives which support the observations. The proton dissociation constants of the compounds were also determined by UV-Vis spectrophotometric and fluorometric titrations to obtain the actual charges and distribution of the species in the various protonation states at physiological pH.

Water-soluble and photo-stable silver(I) dicarboxylate complexes containing 1,10-phenanthroline ligands: Antimicrobial and anticancer chemotherapeutic potential, DNA interactions and antioxidant activity

The complexes [Ag2(OOC-(CH2)n-COO)] (n=1-10) (1-10) were synthesised and reacted with 1,10-phenanthroline (phen) to yield derivatives formulating as [Ag2(phen)x(OOC-(CH2)y-COO)]·zH2O (x=2 or 3; y=1-10; z=1-4) (11-20) which are highly water-soluble and photo-stable in aqueous solution. The phen derivatives 11-20 exhibit chemotherapeutic potential against Candida albicans, Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa and against cisplatin-sensitive breast (MCF-7) and resistant ovarian (SKOV-3) cancer cell lines. Cyclic voltammetric analysis and DNA binding and intercalation studies indicate that the mechanism of action of 11-20 is significantly different to that of their silver(I) dicarboxylate precursors and they do not induce DNA damage or ROS generation in mammalian cells. The representative complexes 9 and 19 (containing the undecanedioate ligand) were both found to significantly reduce superoxide and hydrogen peroxide induced oxidative stress in the yeast S. cerevisiae.

Synthesis, Superoxide Dismutase Mimetic and Anticancer Activities of Metal Complexes of 2,2-Dimethylpentanedioic Acid(2dmepdaH2) and 3,3-Dimethylpentanedioic acid(3dmepdaH2): X-Ray Crystal Structures of [Cu(3dmepda)(bipy)]2· 6H2O and [Cu(2dmepda)(bipy)(EtOH)]2· 4EtOH(bipy = 2,2′Bipyridine)

2,2-dimethylpentanedioic acid (2dmepdaH2) and 3,3-dimethylpentanedioic acid (3dmepdaH2) reacted with copper(II) acetate to give [Cu(2dmepda)(H2O)3]2 (1) and [Cu(3dmepda)(H2O)3]2 (2). Reaction of (1) and (2) with 1,10-phenanthroline and 2,2′-bipyridine yielded [Cu(2dmepda)(phen)(H2O)]20.5phen (3), [Cu(2dmepda)(bipy)(H2O)]2 (4), [Cu(2dmepda)(bipy)(EtOH)]2· 2EtOH (4A), [Cu(3dmepda)(phen)(H2O)]2 (5), and [Cu(3dmepda)(bipy)(H2O)]2· (6). The structures of (4A) and (6) each consists of a [Cu(bipy)(dicarboxylate)(solvent)]2 dimer. The superoxide dismutase (SOD) mimetic activity of the novel copper complexes and their manganese analogues was investigated. The dimethyl sulphoxide(DMSO) soluble complexes (1)–(4) and (6) were assessed for their cancer chemotherapeutic potential towards hepatocellular carcinoma and kidney adenocarcinoma cell lines. The 1,10-phenanthroline containing complex [Cu(2dmepda)(phen)(H2O)]20.5phen (3) was the most potent with activity that compares well to that of cisplatin.

Molecular structure and spectroscopic studies on novel complexes of coumarin-3-carboxylic acid with Ni(II), Co(II), Zn(II) and Mn(II) ions based on density functional theory.

Novel Ni(II), Co(II), Zn(II) and Mn(II) complexes of coumarin-3-carboxylic acid (HCCA) were studied at experimental and theoretical levels. The complexes were characterised by elemental analyses, FT-IR, (1)H NMR, (13)C NMR and UV-Vis spectroscopy and by magnetic susceptibility measurements. The binding modes of the ligand and the spin states of the metal complexes were established by means of molecular modelling of the complexes studied and calculation of their IR, NMR and absorption spectra at DFT(TDDFT)/B3LYP level. The experimental and calculated data verified high spin Ni(II), Co(II) and Mn(II) complexes and a bidentate binding through the carboxylic oxygen atoms (CCA2). The model calculations predicted pseudo octahedral trans-[M(CCA2)(2)(H(2)O)(2)] structures for the Zn(II), Ni(II) and Co(II) complexes and a binuclear [Mn(2)(CCA2)(4)(H(2)O)(2)] structure. Experimental and calculated (1)H, (13)C NMR, IR and UV-Vis data were used to distinguish the two possible bidentate binding modes (CCA1 and CCA2) as well as mononuclear and binuclear structures of the metal complexes.

Non-cytotoxic antibacterial silver-coumarin complex doped sol-gel coatings.

Microbial colonisation on clinical and industrial surfaces is currently of global concern and silane based sol-gel coatings are being proposed as potential solutions. Sol-gels are chemically inert, stable and homogeneous and can be designed to act as a reservoir for releasing antimicrobial agents over extended time periods. In the present study, silver nitrate (AgN) and a series of silver coumarin complexes based on coumarin-3-carboxylatosilver (AgC) and it is 6, 7 and 8 hydroxylated analogues (Ag6, Ag7, Ag8) were incorporated into sol-gel coatings. The comparative antibacterial activity of the coatings was determined against meticillin resistant Staphylococcus aureus (MRSA) and multidrug resistance Enterobacter cloacae WT6. The percentage growth inhibitions were found in the range of 9.2 (±2.7)-66.0 (±1.2)% at low silver loadings of 0.3% (w/w) with E. cloacae being the more susceptible. Results showed that among the Ag coumarin complexes, the Ag8 doped coating had the highest antibiofilm property. XPS confirmed the presence of silver in the nanoparticulate state (Ag(0)) at the coating surface where it remained after 4 days of exposure to bacterial culture. Comparative cytotoxicity studies revealed that the Ag-complex coatings were less toxic than the AgN coating. Thus, it can be concluded that a sol-gel matrix with Ag-coumarin complexes may provide non-toxic surfaces with antibacterial properties.

Spectroscopic studies, DFT calculations, and cytotoxic activity of novel silver(I) complexes of hydroxy ortho-substituted-nitro-2H-chromen-2-one ligands and a phenanthroline adduct.

Silver(I) complexes of coumarin-based ligands and one of their phenanthroline (phen) adducts have been prepared and characterized using microanalytical data, molar conductivity, IR, (1)H and (13)C NMR, UV-Vis, and atomic absorption (AAS) spectroscopies. The binding modes of the coumarin-based ligands and the most probable structure of their Ag(I) complexes were predicted by means of molecular modeling and calculations of their IR, NMR, and absorption spectra using density functional theory (DFT). The cytotoxicity of the compounds studied against human-derived hepatic carcinoma cells (Hep-G2) and a renal cancer cell line (A498) showed that the complexes were more cytotoxic than the clinically used chemotherapeutic, mitoxantrone. The compounds showed little interaction with DNA and also did not show nuclease activity but manifested excellent superoxide dismutase activity which may indicate that their mechanism of action is quite different to many metal-based therapeutics.