Structural and solution speciation studies on selected [Cu(NN)(OO)] complexes and an investigation of their biomimetic activity, ROS generation and their cytotoxicity in normoxic, hypoxic and anoxic environments in MCF-7 breast cancer-derived cells.

Reactive oxygen species(ROS) generation with subsequent DNA damage is one of the principle mechanisms of action assigned to copper-based anticancer complexes. The efficacy of this type of chemotherapeutic may be reduced in the low oxygen environment of tumours. In this study the cytotoxicity of three complexes, [Cu(dips)(phen)] (1), [Cu(ph)(phen)]·2H2O (2) and [Cu(ph)(bpy)]·H2O (3) (disp: 3,5-diisopropylsalicylate, phen: 1,10- phenanthroline, ph: phthalate, bpy: 2,2'-bipyridyl) were assessed for anticancer activity in the breast-cancer derived MCF-7 line under normoxic, hypoxic and anoxic conditions. In an immortalised keratinocyte HaCaT cell line, the cytotoxicity of complexes 2 and 3 was significantly reduced under both normoxic and hypoxic conditions, whilst the cytotoxicity of complex 1 was increased under hypoxic conditions. The ability of the complexes to generate ROS in the MCF-7 cell line was evaluated as was their ability to act as superoxide dismutase(SOD) and catalase mimics using a yeast cell assay. ROS generation was significant for complexes 2 and 3, less so for complex 1 though all three complexes had SOD mimetic ability. Given the ternary nature of the complexes, solution speciation studies were undertaken but were only successful for complex 3, due to solubility issues with the other two complexes. The concentration distribution of various species, formed in aqueous solution, was evaluated as a function of pH and confirmed that complex 3 is the dominant species at physiological pH in the mM concentration range. However, as its concentration diminishes, it experiences a progressive dissociation, leading to the formation of binary complexes of bpy alongside unbound phthalate.

Peptidases Are Potential Targets of Copper(II)-1,10-Phenanthroline-5,6-dione Complex, a Promising and Potent New Drug against Trichomonas vaginalis.

Trichomonas vaginalis is responsible for 156 million new cases per year worldwide. When present asymptomatically, the parasite can lead to serious complications, such as development of cervical and prostate cancer. As infection increases the acquisition and transmission of HIV, the control of trichomoniasis represents an important niche for the discovery and development of new antiparasitic molecules. This urogenital parasite synthesizes several molecules that allow the establishment and pathogenesis of infection. Among them, peptidases occupy key roles as virulence factors, and the inhibition of these enzymes has become an important mechanism for modulating pathogenesis. Based on these premises, our group recently reported the potent anti-T. vaginalis action of the metal-based complex [Cu(phendione)3](ClO4)2.4H2O (Cu-phendione). In the present study, we evaluated the influence of Cu-phendione on the modulation of proteolytic activities produced by T. vaginalis by biochemical and molecular approaches. Cu-phendione showed strong inhibitory potential against T. vaginalis peptidases, especially cysteine- and metallo-type peptidases. The latter revealed a more prominent effect at both the post-transcriptional and post-translational levels. Molecular Docking analysis confirmed the interaction of Cu-phendione, with high binding energy (-9.7 and -10.7 kcal·mol-1, respectively) at the active site of both TvMP50 and TvGP63 metallopeptidases. In addition, Cu-phendione significantly reduced trophozoite-mediated cytolysis in human vaginal (HMVII) and monkey kidney (VERO) epithelial cell lineages. These results highlight the antiparasitic potential of Cu-phendione by interaction with important T. vaginalis virulence factors.

A water-soluble manganese(II) octanediaoate/phenanthroline complex acts as an antioxidant and attenuates alpha-synuclein toxicity.

The overproduction of reactive oxygen species (ROS) induces oxidative stress, a well-known process associated with aging and several human pathologies, such as cancer and neurodegenerative diseases. A large number of synthetic compounds have been described as antioxidant enzyme mimics, capable of eliminating ROS and/or reducing oxidative damage. In this study, we investigated the antioxidant activity of a water-soluble 1,10-phenantroline-octanediaoate Mn2+-complex on cells under oxidative stress, and assessed its capacity to attenuate alpha-synuclein (aSyn) toxicity and aggregation, a process associated with increased oxidative stress. This Mn2+-complex exhibited a significant antioxidant potential, reducing intracelular oxidation and increasing oxidative stress resistance in S. cerevisiae cells and in vivo, in G. mellonella, increasing the activity of the intracellular antioxidant enzymes superoxide dismutase and catalase. Strikingly, the Mn2+-complex reduced both aSyn oligomerization and aggregation in human cell cultures and, using NMR and DFT/molecular docking we confirmed its interaction with the C-terminal region of aSyn. In conclusion, the Mn2+-complex appears as an excellent lead for the design of new phenanthroline derivatives as alternative compounds for preventing oxidative damages and oxidative stress - related diseases.

In Vivo Activity of Metal Complexes Containing 1,10-Phenanthroline and 3,6,9-Trioxaundecanedioate Ligands against Pseudomonas aeruginosa Infection in Galleria mellonella Larvae.

Drug-resistant Pseudomonas aeruginosa is rapidly developing resulting in a serious global threat. Immunocompromised patients are specifically at risk, especially those with cystic fibrosis (CF). Novel metal complexes incorporating 1,10-phenanthroline (phen) ligands have previously demonstrated antibacterial and anti-biofilm effects against resistant P. aeruginosa from CF patients in vitro. Herein, we present the in vivo efficacy of {[Cu(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2]·3H2O·EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4]·EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid). Individual treatments of these metal-tdda-phen complexes and in combination with the established antibiotic gentamicin were evaluated in vivo in larvae of Galleria mellonella infected with clinical isolates and laboratory strains of P. aeruginosa. G. mellonella were able to tolerate all test complexes up to 10 µg/larva. In addition, the immune response was affected by stimulation of immune cells (hemocytes) and genes that encode for immune-related peptides, specifically transferrin and inducible metallo-proteinase inhibitor. The amalgamation of metal-tdda-phen complexes and gentamicin further intensified this response at lower concentrations, clearing a P. aeruginosa infection that were previously resistant to gentamicin alone. Therefore this work highlights the anti-pseudomonal capabilities of metal-tdda-phen complexes alone and combined with gentamicin in an in vivo model.

Anti-Leishmania braziliensis activity of 1,10-phenanthroline-5,6-dione and its Cu(II) and Ag(I) complexes.

Leishmaniasis, included in the priority list of the WHO, remains as a neglected disease caused by parasites of the Leishmania genus. There is no vaccine available for human leishmaniasis, and the current treatment is based on old drugs that cause serious side effects. Herein, we initially studied the cellular distribution of the virulence factor gp63, the major metallopeptidase, in a virulent strain of Leishmania braziliensis, and then we measured the inhibitory effects of 1,10-phenanthroline-5,6-dione (phendione), and its metal complexes, [Cu(phendione)3](ClO4)2.4H2O and [Ag(phendione)2]ClO4, on both cellular and extracellular metallopeptidases produced by promastigotes. The action of the three compounds on parasite viability and on parasite-macrophage interaction was also determined. Gp63 molecules were detected in several parasite compartments, including the cytoplasm, the membrane lining the cell body and flagellum, and in the flagellar pocket, which explains the presence of gp63 in the culture medium. The test compounds inhibited parasite metallopeptidases in a typical dose-dependent manner, and they also caused a significant and irreversible inhibition of parasite motility. Moreover, the pre-treatment of promastigotes with the test compounds induced a decrease in the association index with macrophages. Collectively, phendione and its Cu(II) and Ag(I) complexes are excellent prototypes for the development of new anti-L. braziliensis drugs.

Enhanced pyrazolopyrimidinones cytotoxicity against glioblastoma cells activated by ROS-Generating cold atmospheric plasma.

Pyrazolopyrimidinones are fused nitrogen-containing heterocyclic systems, which act as a core scaffold in many pharmaceutically relevant compounds. Pyrazolopyrimidinones have been demonstrated to be efficient in treating several diseases, including cystic fibrosis, obesity, viral infection and cancer. In this study using glioblastoma U-251MG cell line, we tested the cytotoxic effects of 15 pyrazolopyrimidinones, synthesised via a two-step process, in combination with cold atmospheric plasma (CAP). CAP is an adjustable source of reactive oxygen and nitrogen species as well as other unique chemical and physical effects which has been successfully tested as an innovative cancer therapy in clinical trials. Significantly variable cytotoxicity was observed with IC50 values ranging from around 11 µM to negligible toxicity among tested compounds. Interestingly, two pyrazolopyrimidinones were identified that act in a prodrug fashion and display around 5-15 times enhanced reactive-species dependent cytotoxicity when combined with cold atmospheric plasma. Activation was evident for direct CAP treatment on U-251MG cells loaded with the pyrazolopyrimidinone and indirect CAP treatment of the pyrazolopyrimidinone in media before adding to cells. Our results demonstrated the potential of CAP combined with pyrazolopyrimidinones as a programmable cytotoxic therapy and provide screened scaffolds that can be used for further development of pyrazolopyrimidinone prodrug derivatives.

Influence of molecular weight fractionation on the antimicrobial and anticancer properties of a fucoidan rich-extract from the macroalgae Fucus vesiculosus.

The objective of this study was to investigate the antimicrobial and anticancer properties of a fucoidan extract and subsequent fractions isolated from the macroalgae Fucus vesiculosus. The fractions obtained (>300 kDa, <300 kDa, <100 kDa, <50 kDa and <10 kDa) could inhibit the growth of B. subtilis, E. coli, L. innocua and P. fluorescens when assayed at concentrations between 12,500 and 25,000 ppm. The bacterial growth was monitored by optical density (OD) measurements (600 nm, 24 h) at 30 °C or 37 °C, depending upon on the strain used. The extracted fractions were also tested for cytotoxicity against brain glioblastoma cancer cells using the Alamar Blue assay for 24 h, 48 h and 6 days. The >300 kDa fraction presented the lowest IC50 values (0.052% - 24 h; 0.032% - 6 days). The potential bioactivity of fucoidan as an antimicrobial and anticancer agent was demonstrated in this study. Hence, the related mechanisms of action should be explored in a near future.

The Antibacterial and Anti-biofilm Activity of Metal Complexes Incorporating 3,6,9-Trioxaundecanedioate and 1,10-Phenanthroline Ligands in Clinical Isolates of Pseudomonas Aeruginosa from Irish Cystic Fibrosis Patients.

Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis (CF) patients are problematic in Ireland where inherited CF is prevalent. The bacteria's capacity to form a biofilm in its pathogenesis is highly virulent and leads to decreased susceptibility to most antibiotic treatments. Herein, we present the activity profiles of the Cu(II), Mn(II) and Ag(I) tdda-phen chelate complexes {[Cu(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Cu-tdda-phen), {[Mn(3,6,9-tdda)(phen)2].3H2O.EtOH}n (Mn-tdda-phen) and [Ag2(3,6,9-tdda)(phen)4].EtOH (Ag-tdda-phen) (tddaH2 = 3,6,9-trioxaundecanedioic acid; phen = 1,10-phenanthroline) towards clinical isolates of P. aeruginosa derived from Irish CF patients in comparison to two reference laboratory strains (ATCC 27853 and PAO1). The effects of the metal-tdda-phen complexes and gentamicin on planktonic growth, biofilm formation (pre-treatment) and mature biofilm (post-treatment) alone and in combination were investigated. The effects of the metal-tdda-phen complexes on the individual biofilm components; exopolysaccharide, extracellular DNA (eDNA), pyocyanin and pyoverdine are also presented. All three metal-tdda-phen complexes showed comparable and often superior activity to gentamicin in the CF strains, compared to their activities in the laboratory strains, with respect to both biofilm formation and established biofilms. Combination studies presented synergistic activity between all three complexes and gentamicin, particularly for the post-treatment of established mature biofilms, and was supported by the reduction of the individual biofilm components examined.

Pt(IV) pro-drugs with an axial HDAC inhibitor demonstrate multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance in A2780/A2780cis cells.

Epigenetic agents such as histone deacetylase (HDAC) inhibitors are widely investigated for use in combined anticancer therapy and the co-administration of Pt drugs with HDAC inhibitors has shown promise for the treatment of resistant cancers. Coordination of an HDAC inhibitor to an axial position of a Pt(IV) derivative of cisplatin allows the combination of the epigenetic drug and the Pt chemotherapeutic into a single molecule. In this work we carry out mechanistic studies on the known Pt(IV) complex cis,cis,trans-[Pt(NH3)2Cl2(PBA)2] (B) with the HDAC inhibitor 4-phenylbutyrate (PBA) and its derivatives cis,cis,trans-[Pt(NH3)2Cl2(PBA)(OH)] (A), cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Bz)] (C), and cis,cis,trans-[Pt(NH3)2Cl2(PBA)(Suc)] (D) (Bz = benzoate, Suc = succinate). The comparison of the cytotoxicity, effect on HDAC activity, reactive oxygen species (ROS) generation, γ-H2AX (histone 2A-family member X) foci generation and induction of apoptosis in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells shows that A - C exhibit multimodal mechanisms involving DNA damage and apoptosis independent of cisplatin resistance.

Cu(ii) phenanthroline-phenazine complexes dysregulate mitochondrial function and stimulate apoptosis.

Herein we report an in-depth study on the cytotoxic mechanism of action of four developmental cytotoxic copper(ii) complexes: [Cu(phen)2]2+ (Cu-Phen); [Cu(DPQ)(Phen)]2+ (Cu-DPQ-Phen); [Cu(DPPZ)(Phen)]2+; and [Cu(DPPN)(Phen)]2+ (where Phen = 1,10-phenanthroline, DPQ = dipyrido[3,2-f:2',3'-h]quinoxaline, DPPZ = dipyrido[3,2-a:2',3'-c]phenazine, and DPPN = benzo[i]dipyrido[3,2-a:2',3'-c]phenazine). This complex class is known for its DNA intercalative properties and recent evidence-derived from an in vivo proteomic study-supports the potential targeting of mitochondrial function. Therefore, we focused on mitochondrial-mediated apoptosis related to cytotoxic activity and the potential impact these agents have on mitochondrial function. The Cu(ii) complexes demonstrated superior activity regardless of aromatic extension within the phenazine ligand to the previously demonstrated activity of cisplatin. Unique toxicity mechanisms were also identified in prior demonstrated cisplatin sensitive and resistant cell lines. Double strand breaks in genomic DNA, quantified by γH2AX foci formation, were then coupled with apoptotic gene expression to elucidate the mechanisms of cell death. These results indicate that while DNA damage-induced apoptosis by BAX, XIAP and caspase-9 and -3 expression is moderate for the Cu(ii) complexes when compared to cisplatin, protein targets independent of DNA exert a multimodal mechanistic effect. Significantly, mitochondrial gene expression of oxidative stress, protease expression, and fission/fusion processes-upregulated HMOX, DRP1 and LON, respectively-indicated an increased oxidative damage associated with compromised mitochondrial health upon exposure to these agents. These data support a unique mode of action by these complexes and provide valuable evidence of the developmental potential of these therapeutic inorganic complexes.

Copper(II) complexes of coumarin-derived Schiff base ligands: Pro- or antioxidant activity in MCF-7 cells?

A series of copper(II) complexes of Schiff base-derived ligands (1-7) were studied for their pro- and antioxidant behaviour in the MCF-7 human breast cancer cell line. The coordination modes of two of the copper(II) complexes were investigated by pH-potentiometry, EPR and UV-Vis spectroscopic methods. The solution studies indicated that monomeric species are present in the Cu(II) - L1 system at neutral pH, whereas dinuclear species were observed in the case of the Cu(II) - L7 system. This difference in speciation was reflected in their relative cytotoxicities with the copper(II) complex of L1, showing significant cytotoxicity against MCF-7 cells whilst the complex of L7 was inactive. In fact, only three of the seven complexes studied in this series were cytotoxic to MCF-7 cells but this cytotoxicity did not correlate with their ability to bind to DNA, cleave DNA or act as a pro-oxidant. In contrast to previous copper(II) complexes studied by our group, the compounds studied here do not appear to lead to intracellular reactive oxygen species generation at any significant level. In a yeast-based assay, all of the copper complexes had the ability to protect Saccharomyces cerevisiae against menadione-induced oxidative stress but not hydrogen peroxide-induced stress, indicating a lack of catalase activity. Given that the adaptive mechanisms induced by hypoxia in cancer cells have selective effects, with a fine-tuned protection against damage and stress of many kinds, particularly against oxidative stress, chemotherapeutic compounds which are not pro-oxidants may offer a therapeutic advantage.

Targeting the Folate Receptor: Improving Efficacy in Inorganic Medicinal Chemistry.

The discovery of the high-affinity, high-specificity folate receptor in mamalian kidney cells, coupled with the ability of folate to enter cells by folate receptor-mediated endocytosis and the subsequent elucidation of the folate receptor's overexpression in specific cancer cell types; heralded the arrival of the area of chemotherapeutic folate targeting. The application of purely organic folate-based small-molecule drug conjugates that selectively target the folate receptor, which is over expressed in several diseases such as cancer, is well established. The application of inorganic folate-targeted drugs offers significant potential to expand and enhance this therapeutic approach. From the data made available to date, it is apparent that this aspect of inorganic medicinal chemistry is in its youth but has the capability to contribute greatly to cancer research, both in therapy and diagnosis. The union of folate-receptor targeting and inorganic medicine may also lead to the development of treatments for disorders such as chronic-inflammation, tuberculosis, neurodegenerative disease and leishmaniasis. In this review, we summarize what is known about the coordination chemistry of folic acid and the therapeutic potential of such complexes. We also describe approaches adopted to conjugate platinum drugs to folate- or folate-carrier- systems and their prospective ability to overcome problems associated with unwanted side-effects and resistance by improving their delivery and/or selectivity. The literature pertaining to non-platinum metal complex conjugates with folic acid is also reviewed revealing that this is an area that offers significant potential to develop targeted therapeutic approaches in areas such as chemotherapy and molecular imaging for diagnostics.

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.

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.

Potent oxidative DNA cleavage by the di-copper cytotoxin: [Cu2(µ-terephthalate)(1,10-phen)4]2+.

The di-copper(II) cation, [Cu(2)(µ-terephthalate)(1,10-phen)(4)](2+), is a powerful, non-sequence-specific, minor-groove oxidizer of duplex DNA which, unlike copper(II) bis-1,10-phenanthroline chloride, operates independently of exogenous reagents. The agent displays excellent in vitro cytoxicity towards cisplatin-resistant ovarian cancer cells, producing intracellular reactive oxygen species upon nano-molar exposure.

Radical-induced DNA damage by cytotoxic square-planar copper(II) complexes incorporating o-phthalate and 1,10-phenanthroline or 2,2'-dipyridyl.

DNA-targeting copper(II) reagents have emerged as suitable drug candidates owing to the clinical success of the copper-activated, natural chemotherapeutic drug bleomycin. This agent and the synthetic chemical nuclease copper(II) bis-1,10-phenanthroline represent important templates for inorganic drug design owing to their ability to initiate free radical DNA scission. Herein, we report the synthesis and biological properties of 1:1:1 square-planar copper(II) complexes incorporating the dicarboxylate o-phthalate and 1,10-phenanthroline (1) or 2,2'-dipyridyl (2) ligands. Their broad-spectrum chemotherapeutic potential has been assessed at 24- and 96-h intervals, along with that of the clinical agent cisplatin, using breast (MCF-7), prostate (DU145), colon (HT29), and intrinsically cisplatin-resistant ovarian (SK-OV-3) human cancer cells. 1 represents a potent cytotoxic agent with IC(50) values ranging from 5.6 to 3.4µM across all cell lines, including SK-OV-3. The production of endogenous reactive oxygen species within SK-OV-3 cancer cells was monitored using the fluorophore 2',7'-dichlorodihydrofluorescin diacetate, and results indicate a concentration-dependent propensity toward ROS generation by 1 and 2 that mirrors their antitumoral behavior. DNA interaction studies, using fluorescence and viscosity measurements, were conducted in tandem with the DNA-targeting drugs actinomycin D and pentamidine, using calf thymus DNA, poly[d(A-T)(2)], and poly[d(G-C)(2)], with intercalation of 1 and 2 at the minor groove appearing to be the likely interaction mode. DNA cleavage reactions using superhelical plasmid DNA, in the presence of exogenous reductant, l-ascorbic acid, revealed excellent agreement between double-stranded DNA scission capability and antitumoral IC(50) concentration. The presence of double-strand DNA breaks (DSBs) was confirmed within SK-OV-3 cancer cells using immunodetection of γ-H2AX foci by confocal microscopy and flow cytometry, with complex 1 quantitatively producing superior numbers of DSBs compared with complex 2. Superoxide dismutase and catalase mimetic activity assays were conducted, and these activities are related to the ability of both complexes to cleave DNA through free radical generation.

Copper(II) complexes of salicylic acid combining superoxide dismutase mimetic properties with DNA binding and cleaving capabilities display promising chemotherapeutic potential with fast acting in vitro cytotoxicity against cisplatin sensitive and resistant cancer cell lines.

The complexes [Cu(salH)(2)(H(2)O)] (1), [Cu(dipsH)(2)(H(2)O)] (2), {Cu(3-MeOsal)(H(2)O)(0.75)}(n) (3), [Cu(dipsH)(2)(BZDH)(2)] (4), [Cu(dipsH)(2)(2-MeOHBZDH)(2)]·EtOH (5), [Cu(sal)(phen)] (6), [Cu(dips)(phen)]·H(2)O (7), and [Cu(3-MeOsal)(phen)]·H(2)O (8) (salH(2) = salicylic acid; dipsH(2) = 3,5-diisopropylsalicylic acid; 3-MeOsalH(2) = 3-methoxysalicylic acid; BZDH = benzimidazole; 2-MeOHBZDH = 2 methanolbenzimidazole and phen =1,10-phenanthroline) were prepared and characterized. Structures of 4, 5, and 8 were determined by X-ray crystallography. Compounds 1-8 are potent superoxide dismutase mimetics, and they are inactive as inhibitors of COX-2 activity. Compounds 1, 4, and 5 exhibit moderate inhibition of COX-1. Complexes 6-8 display rapid micromolar cytotoxicity against cisplatin sensitive (breast (MCF-7), prostate (DU145), and colon (HT29)) and cisplatin resistant (ovarian (SK-OV-3)) cell lines compared to 1-5, and they exhibit potent in vitro DNA binding and cleavage capabilities.

Bis-phenanthroline copper(II) phthalate complexes are potent in vitro antitumour agents with 'self-activating' metallo-nuclease and DNA binding properties.

Three, structurally characterised, bis-phen Cu(II) complexes of the phthalate isomers display rapid, low micromolar in vitro cytotoxicity against a range of epithelial tumour cells. The complexes induce relaxation of supercoiled plasmid DNA in the absence of external reducing agents and display efficient CT-DNA, Poly[d(A-T)](2) and Poly[d(G-C)](2) binding.

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.