Malachy McCann

National University of Ireland, Maynooth, Maigh Nuad, Leinster, Ireland

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Publications (101)240.15 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Here we report the synthesis and isolation of a series of bis-chelate Cu(2+) phenanthroline-phenazine cationic complexes of [Cu(DPQ)(Phen)](2+), [Cu(DPPZ)(Phen)](2+), and [Cu(DPPN)(Phen)](2+) (where Phen = 1,10-phenanthroline, DPQ = dipyridoquinoxaline, DPPZ = dipyridophenazine, and DPPN = benzo[i]dipyridophenazine). These compounds have enhanced DNA recognition relative to the well-studied chemical nuclease, [Cu(Phen)2](2+) (bis-Phen), with calf thymus DNA binding constants of DPQ and DPPZ agents (∼10(7) M(bp)(-1)) being the highest currently known for Cu(2+) phenanthrene compounds. Complex DNA binding follows DPQ ≈ DPPZ > DPPN > bis-Phen, with fluorescence quenching and thermal melting experiments on poly[d(A-T)2] and poly[d(G-C)2] supporting intercalation at both the minor and major groove. Phenazine complexes, however, show enhanced targeting and oxidative cleavage on cytosine-phosphate-guanine-rich DNA and have comparable in vitro cytotoxicity toward the cisplatin-resistant ovarian cancer line, SKOV3, as the clinical oxidative DNA-damaging drug doxorubicin (Adriamycin). In this study we also describe how a novel "on-chip" method devised for the Bioanalyser 2100 was employed to quantify double-stranded DNA damage, with high precision, by the complex series on pUC19 DNA (49% A-T, 51% G-C). Both DPQ and bis-Phen complexes are highly efficient oxidizers of pUC19, with DPQ being the most active of the overall series. It is apparent, therefore, that oxidative chemical nuclease activity on homogeneous canonical DNA is not entirely dependent on dynamic nucleotide binding affinity or intercalation, and this observation is corroborated through catalytic interactions with the superoxide anion radical and Fenton breakdown of hydrogen peroxide.
    Inorganic Chemistry 05/2014; · 4.59 Impact Factor
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    ABSTRACT: The synthetic chemical nuclease, [Cu(1,10-phenanthroline)2](2+), has stimulated research within metallonuclease development and in the area of cytotoxic metallodrug design. Our analysis reveals, however, that this agent is "promiscuous" as it binds both dsDNA and protein biomolecules, without specificity, and induces general toxicity to a diversity of cell lineages. Here, we describe the synthesis and characterisation of small-molecule metallonucleases containing the redox-active cation; [Cu(RCOO)(1,10-phen)2](+), where 1,10-phen = 1,10-phenanthroline and R = -H, -CH3, -C2H5, -CH(CH3)2 and -C(CH3)3. The presence of coordinated carboxylate groups in the complex cation function to enhance dsDNA recognition, reduce serum albumin binding and offer control of toxicity toward human cancer cells, gram positive and negative bacteria and fungal pathogens. The induction of genomic dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells using immunodetection of γ-H2AX. Formate, acetate and pivalate functionalised complexes induced DSBs in a higher percentage of cells compared with [Cu(1,10-phen)2](2+) which supports the importance of inner-sphere modification toward enhancing targeted biological application.
    Journal of Medicinal Chemistry 10/2013; · 5.61 Impact Factor
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    Alanna Smith, Malachy McCann, Kevin Kavanagh
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    ABSTRACT: The silver ion (Ag (I)) has well established antimicrobial properties and is widely used in a variety of anti-bacterial ointments and plasters for the control of wound infections. Wounds are frequently colonized by the bacterium Staphylococcus aureus and the aim of the work presented here was to establish how S. aureus responded following exposure to Ag(I). Exposure of S. aureus to Ag(I) resulted in the release of a range of proteins from cells. Analysis of proteins released revealed a number of proteins associated with the stress response (e.g. alkaline shock protein, methionine sulfoxide reductase), virulence (e.g. signal transduction protein) and metabolism (e.g. lipase, acetate kinase, phosphoglycerate mutase). The release of toxins (e.g.α-hemolysin, bifunctional autolysin, leucocidin F) was decreased. These results indicated that, while silver is a potent antimicrobial agent, exposure of S. aureus to this metal results in the release of a variety of proteins from the cell. Many of the proteins showing increased release were antigenic and would have the potential to induce an inflammatory response at the site of infection and thus delay healing.
    Toxicology in Vitro 04/2013; · 2.65 Impact Factor
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    ABSTRACT: Limitations associated with the production cost, metabolic instability, side-effects, resistance and poor pharmacokinetics of organic protease inhibitors (PIs), which form an essential component of the front line HAART treatment for HIV, have fuelled efforts into finding novel, transition metal-based alternatives. Some of the attractive features of metal-based therapeutics include synthetic simplicity, solubility control, redox capability, expansion of coordination number and topography matching of the complex to the protein's active site. Building asymmetry into the complex, which may offer better discrimination between host and rogue cell, can readily be achieved through coordination of chiral ligands to the metal centre. Although the scope of this review has been limited to metal-based agents that have been reported to bind/inhibit HIV-1 and parasitic proteases, some desirables, such as high activity, low dosage, minimal toxicity, cross-inhibition, unique binding modes and selectivity, have already been delivered. The variability of the d-block metals, coupled with the availability of designer organic ligands, augers well for the future development of clinical metallo-drugs for deployment against protease-associated, fatal diseases.
    Current Medicinal Chemistry 03/2013; · 3.72 Impact Factor
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    ABSTRACT: 1,10-Phenanthroline-5,6-dione and l-tyrosine methyl ester react to form phenanthroline-oxazine (PDT) from which [Cu(PDT)(2)](ClO(4))(2) and [Ag(PDT)(2)]ClO(4)·2MeOH are obtained. Binding to calf-thymus DNA by Ag(i) and Cu(ii) PDT complexes exceed bis-1,10-phenanthroline analogues and the minor groove binding drugs, pentamidine and netropsin. Furthermore, unlike the artificial metallonuclease, [Cu(phen)(2)](2+), the [Cu(PDT)(2)](2+) complex does not cleave DNA in the presence of added reductant indicating unique interaction with DNA.
    Chemical Communications 02/2013; 49(23):2341-3. · 6.38 Impact Factor
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    ABSTRACT: In vitro and in vivo studies into the biological activities of 1,10-phenanthroline, 1,10-phenanthroline-5,6-dione and its copper(II) and silver(I) complexes 1,10-Phenanthroline (phen, 5), 1,10-phenanthroline-5,6-dione (phendione, 6), [Cu(phendione) 3 ]-(ClO 4) 2 ·4H 2 O (12) and [Ag(phendione) 2 ]ClO 4 (13) are highly active, in vitro, against a range of normal and cancerous mammalian cells, fungal and insect cell lines, with the metal complexes offering a clear enhancement in activity. Cytoselectivity was not observed between the tumorigenic and non-tumorigenic mammalian lines. In in vivo tests, using Galleria mellonella and Swiss mice, all four compounds were well tolerated in comparison to the clinical agent, cisplatin. In addition, blood samples taken from the Swiss mice showed that the levels of the hepatic enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT), remained unaffected. Immunocompromised nude mice showed a much lower tolerance to 13 and, subsequently, when these mice were implanted with Hep-G2 (hepatic) and HCT-8 (colon) human-derived tumors, there was no influence on tumor growth.
    Toxicology Research. 07/2012; 1(1-1):47.
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    ABSTRACT: 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.
    Chemical Communications 06/2012; 48(55):6906-8. · 6.38 Impact Factor
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    ABSTRACT: 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.
    Free Radical Biology & Medicine 05/2012; 53(3):564-76. · 5.27 Impact Factor
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    ABSTRACT: The Ag(I) ion has well established anti-bacterial and antifungal properties. Exposure of Staphylococcus aureus to MIC(80) AgNO(3) (3 μg/ml) lead to an increase in the activity of superoxide dismutase, glutathione reductase and catalase at 30 min but activity declined by 60 min. In addition, exposure of cells to this metal ion for 1 h lead to increased expression of a number of proteins such as elongation factors Ts, Tu and G, fructose-bisphosphate aldolase and triosephosphate isomerase but their expression declined following 4 h exposure. ATP binding cassette transporter protein and oligoendopeptidase F showed increased expression at 4 h. While Ag(I) is a potent antimicrobial agent this work demonstrates that S. aureus can mount a short-term protective response to exposure to the metal ion but that this is eventually overcome.
    Biology of Metals 04/2012; 25(3):611-6. · 3.17 Impact Factor
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    ABSTRACT: [Ag(2)(9-aca)(2)] (1) (9-acaH = 9-anthracenecarboxylic acid) reacts with a series of imidazoles to give [Ag(imidH)(2.3)(CH(3)CN)(0.7)](9-aca) (3), [Ag(6)(imidH)(4)(9-aca)(6)(MeOH)(2)] (4), {[Ag(1-Me-imid)(2)](2)[Ag(4)(9-aca)(6)]} (5), {[Ag(1-Bu-imid)(2)](2)[Ag(4)(9-aca)(6)]} (6) and [Ag(apim)](9-aca)·H(2)O (7) (imidH = imidazole; 1-Me-imid = 1-methylimidazole; 1-Bu-imid = 1-butylimidazole; apim = 1-(3-aminopropyl)imidazole). The mononuclear complex 3, hexanuclear 4-6, and polymeric 7, were all characterised using X-ray crystallography. While many of the complexes possess excellent in vitro antifungal and antibacterial activities they are, unanimously, more effective against fungal cells. The insect, Galleria mellonella, can survive high doses of the Ag(i) complexes administered in vivo, and a number of the complexes offer significant protection to larvae infected with a lethal dose of pathogenic Candida albicans cells.
    Dalton Transactions 04/2012; 41(21):6516-27. · 3.81 Impact Factor
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    ABSTRACT: The opportunistic fungal pathogen, Candida albicans, causes a range of diseases in susceptible individuals. The adverse side effects of many of the current anti-fungal prescription drugs and the emergence of C. albicans isolates and other Candida species which are resistant to these compounds have accelerated the search for new drug candidates which have different modes of action. A family of metal chelators, which are based on the 1,10-phenanthroline core, exhibit excellent growth inhibitory effects in vitro against a number of Candida species, including clinical isolates. The compounds sequester transition metal ions, damage mitochondrial function and uncouple cell respiration. Additionally, fungal cell morphology undergoes dramatic changes and there is evidence of apoptotic cell death. Importantly, in vivo studies have confirmed that the compounds have an acceptably low toxicity profile.
    Current Medicinal Chemistry 03/2012; 19(17):2703-14. · 3.72 Impact Factor
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    ABSTRACT: Infections caused by resistant microorganisms often fail to respond to conventional therapy, resulting in prolonged illness, increased treatment costs and greater risk of death. Consequently, the development of novel antimicrobial drugs is becoming more demanding every day since the existing drugs either have too many side-effects or they tend to lose effectiveness due to the selection of resistant strains. In view of these facts, a number of new strategies to obstruct vital biological processes of a microbial cell have emerged; one of these is focused on the use of metal-chelating agents, which are able to selectively disturb the essential metal metabolism of the microorganism by interfering with metal acquisition and bioavailability for crucial reactions. The chelation activity is able to inhibit the biological role of metal-dependent proteins (e.g., metalloproteases and transcription factors), disturbing the microbial cell homeostasis and culminating in the blockage of microbial nutrition, growth and development, cellular differentiation, adhesion to biotic (e.g., extracellular matrix components, cell and/or tissue) and abiotic (e.g., plastic, silicone and acrylic) structures as well as controlling the in vivo infection progression. Interestingly, chelating agents also potentiate the activity of classical antimicrobial compounds. The differences between the microorganism and host in terms of the behavior displayed in the presence of chelating agents could provide exploitable targets for the development of an effective chemotherapy for these diseases. Consequently, metal chelators represent a novel group of antimicrobial agents with potential therapeutic applications. This review will focus on the anti-fungal and anti-protozoan action of the most common chelating agents, deciphering and discussing their mode of action.
    Current Medicinal Chemistry 03/2012; 19(17):2715-37. · 3.72 Impact Factor
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    ABSTRACT: 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.
    Journal of Medicinal Chemistry 03/2012; 55(5):1957-68. · 5.61 Impact Factor
  • International journal of clinical pharmacology and therapeutics 01/2012; 50(1):79-81. · 1.20 Impact Factor
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    ABSTRACT: 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.
    Spectrochimica Acta Part A Molecular and Biomolecular Spectroscopy 12/2011; 84(1):275-85. · 1.98 Impact Factor
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    ABSTRACT: Dinuclear Cu2+ and Mn2+ bis-phenanthroline octanedioate compounds exhibit rapid, unprecedented nano and picomolar in vitro cytotoxicity against human-derived colorectal cancer lines (HT29, SW480 and SW620) and are less cytotoxic toward non-cancerous normal human keratinocytecells (HaCaT). Both complexes displayed greater in vivo drug tolerance compared to cisplatin when examined using the insect Galleria mellonella. The compounds are potent generators of intracellularreactive oxygen species within HT29cells, display avid DNA binding and induce O2-dependent cleavage of supercoiled pUC18DNA. The Cu2+ complex was found to display self-cleaving nuclease activity and a mechanism of deoxyribose C–H bond activation is proposed, based on interactions with the superoxide anion and hydrogen peroxide along with DNA cleavage observations under anaerobic conditions and with an excess of the metal chelatorEDTA.
    Medicinal Chemistry Communication 07/2011; · 2.72 Impact Factor
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    ABSTRACT: 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.
    Dalton Transactions 02/2011; 40(5):1024-7. · 3.81 Impact Factor
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    ABSTRACT: The structures of [Cu(AA)(6)](ClO(4))(2), (I), and [Mn(AA)(6)](ClO(4))(2), (II) (AA is acrylamide, also known as prop-2-enamide; C(3)H(5)NO), display both intra- and intermolecular N-H...O hydrogen bonding. A three-dimensional network is propagated via the perchlorate counter-ions. There are two crystallographically independent molecules in the copper complex, with the most significant difference between them being the conformation of one symmetry-related pair of AA ligands which are in the unusual syn conformation. The copper complex exhibits syn/anti disorder of the =CH(2) group in one pair of symmetry-related AA ligands. The Cu(II) and Mn(II) centres are both situated on centres of inversion. The copper complex cation has octahedral coordination geometry with typical Jahn-Teller distortions.
    Acta Crystallographica Section C Crystal Structure Communications 11/2010; 66(Pt 11):m358-62. · 0.78 Impact Factor
  • Raymond Rowan, Malachy McCann, Kevin Kavanagh
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    ABSTRACT: The response of the pathogenic yeast Candida albicans to the silver(I) perchlorate salt (AgClO(4)) was assessed. By employing an anti-phospho-p38 MAPK antibody, dual phosphorylation of a high osmolarity protein (Hog1p) in C. albicans in the presence of AgClO(4) was demonstrated. Phosphorylation of C. albicans Hog1p in response to hydrogen peroxide or AgClO(4) resulted in the translocation of this mitogen-activated protein (MAP) kinase to the nucleus. Nuclear translocation of C. albicans activating protein-1 (Cap1p) was demonstrated by Western blot analysis and detected using polyclonal anti-Cap1p antibody. Upon AgClO(4)-induced translocation of Cap1p there was a concomitant activation of genes coding for glutathione reductase-1 and Mn-superoxide dismutase but no increase in the expression of flavin oxidoreductase or mitochondrial processing protease was recorded. In addition, exposure to AgClO(4) increased the activity of superoxide dismutase, glutathione reductase and catalase. The activation of C. albicans oxidative stress response genes and enzymes following exposure to AgClO(4) is evidence of the generation of oxidative stress within this medically important yeast.
    Medical mycology: official publication of the International Society for Human and Animal Mycology 05/2010; 48(3):498-505. · 2.13 Impact Factor
  • ChemInform 01/2010; 27(4).

Publication Stats

409 Citations
240.15 Total Impact Points

Institutions

  • 2000–2014
    • National University of Ireland, Maynooth
      • • Department of Chemistry
      • • Department of Biology
      Maigh Nuad, Leinster, Ireland
  • 2012–2013
    • Dublin City University
      • School of Chemical Sciences
      Dublin, L, Ireland
  • 1995–2012
    • Dublin Institute of Technology
      Dublin, Leinster, Ireland
  • 2007–2009
    • Institute of Technology Tallaght
      • • Department of Applied Science
      • • Centre for Pharmaceutical Research and Development (CPRD)
      Dublin, L, Ireland
  • 1991–1999
    • Saint Patrick's College, Maynooth
      Maigh Nuad, Leinster, Ireland
  • 1997
    • St Patrick's College
      Londinium, England, United Kingdom
    • Queen's University Belfast
      Béal Feirste, N Ireland, United Kingdom
  • 1996
    • University of Reading
      • Department of Chemistry
      Reading, ENG, United Kingdom
    • Queen's University
      Kingston, Ontario, Canada
  • 1991–1995
    • University of Guelph
      • Department of Chemistry
      Guelph, Ontario, Canada
  • 1993–1994
    • Trinity College Dublin
      • School of Chemistry
      Dublin, L, Ireland