School of Chemistry - Research Publications

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    Diacetylbis(N(4)-methylthiosemicarbazonato) Copper(II) (CuII(atsm)) Protects against Peroxynitrite-induced Nitrosative Damage and Prolongs Survival in Amyotrophic Lateral Sclerosis Mouse Model
    Soon, CPW ; Donnelly, PS ; Turner, BJ ; Hung, LW ; Crouch, PJ ; Sherratt, NA ; Tan, J-L ; Lim, NK-H ; Lam, L ; Bica, L ; Lim, S ; Hickey, JL ; Morizzi, J ; Powell, A ; Finkelstein, DI ; Culvenor, JG ; Masters, CL ; Duce, J ; White, AR ; Barnham, KJ ; Li, Q-X (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-12-23)
    Amyotrophic lateral sclerosis (ALS) is a progressive paralyzing disease characterized by tissue oxidative damage and motor neuron degeneration. This study investigated the in vivo effect of diacetylbis(N(4)-methylthiosemicarbazonato) copper(II) (CuII(atsm)), which is an orally bioavailable, blood-brain barrier-permeable complex. In vitro the compound inhibits the action of peroxynitrite on Cu,Zn-superoxide dismutase (SOD1) and subsequent nitration of cellular proteins. Oral treatment of transgenic SOD1G93A mice with CuII(atsm) at presymptomatic and symptomatic ages was performed. The mice were examined for improvement in lifespan and motor function, as well as histological and biochemical changes to key disease markers. Systemic treatment of SOD1G93A mice significantly delayed onset of paralysis and prolonged lifespan, even when administered to symptomatic animals. Consistent with the properties of this compound, treated mice had reduced protein nitration and carbonylation, as well as increased antioxidant activity in spinal cord. Treatment also significantly preserved motor neurons and attenuated astrocyte and microglial activation in mice. Furthermore, CuII(atsm) prevented the accumulation of abnormally phosphorylated and fragmented TAR DNA-binding protein-43 (TDP-43) in spinal cord, a protein pivotal to the development of ALS. CuII(atsm) therefore represents a potential new class of neuroprotective agents targeting multiple major disease pathways of motor neurons with therapeutic potential for ALS.
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    Cellular Up-regulation of Nedd4 Family Interacting Protein 1 (Ndfip1) using Low Levels of Bioactive Cobalt Complexes
    Schieber, C ; Howitt, J ; Putz, U ; White, JM ; Parish, CL ; Donnelly, PS ; Tan, S-S (AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC, 2011-03-11)
    The delivery of metal ions using cell membrane-permeable metal complexes represents a method for activating cellular pathways. Here, we report the synthesis and characterization of new [Co(III)(salen)(acac)] complexes capable of up-regulating the ubiquitin ligase adaptor protein Ndfip1. Ndfip1 is a neuroprotective protein that is up-regulated in the brain after injury and functions in combination with Nedd4 ligases to ubiquitinate harmful proteins for removal. We previously showed that Ndfip1 can be increased in human neurons using CoCl(2) that is toxic at high concentration. Here we demonstrate a similar effect can be achieved by low concentrations of synthetic Co(III) complexes that are non-toxic and designed to be activated following cellular entry. Activation is achieved by intracellular reduction of Co(III) to Co(II) leading to release of Co(II) ions for Ndfip1 up-regulation. The cellular benefit of Ndfip1 up-regulation by Co(III) complexes includes demonstrable protection against cell death in SH-SY5Y cells during stress. In vivo, focal delivery of Co(III) complexes into the adult mouse brain was observed to up-regulate Ndfip1 in neurons. These results demonstrate that a cellular response pathway can be advantageously manipulated by chemical modification of metal complexes, and represents a significant step of harnessing low concentration metal complexes for therapeutic benefit.
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    Tunable Porous Coordination Polymers for the Capture, Recovery and Storage of Inhalation Anesthetics
    Abrahams, BF ; Dharma, AD ; Donnelly, PS ; Hudson, TA ; Kepert, CJ ; Robson, R ; Southon, PD ; White, KF (Wiley, 2017-06-12)
    The uptake of inhalation anesthetics by three topologically identical frameworks is described. The 3D network materials, which possess square channels of different dimensions, are formed from the relatively simple combination of ZnII centres and dianionic ligands that contain a phenolate and a carboxylate group at opposite ends. All three framework materials are able to adsorb N2O, Xe and isoflurane. Whereas the framework with the widest channels is able to adsorb large quantities of the various guests from the gas phase, the frameworks with the narrower channels have superior binding enthalpies and exhibit higher levels of retention. The use of ligands in which substituents are bound to the aromatic rings of the bridging ligands offers great scope for tuning the adsorption properties of the framework materials.
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    Guest‐induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes
    Paterson, BM ; White, KF ; White, JM ; Abrahams, BF ; Donnelly, PS (Wiley, 2017-07-10)
    Abstract A ZnII complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal‐bis(4‐phenyl‐3‐thiosemicarbazone) (H2gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO2, CS2, or CH3CN leads to the formation of [4+4] open‐ended charge‐neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO2 with an isosteric enthalpy of sorption of 28 kJ mol−1 at low loading.
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    Guest-induced Assembly of Bis(thiosemicarbazonato) Zinc(II) Coordination Nanotubes
    Paterson, BM ; White, KF ; White, JM ; Abrahams, BF ; Donnelly, PS (Wiley, 2017-07-10)
    A ZnII complex of the dianionic tetradentate ligand formed by deprotonation of glyoxal‐bis(4‐phenyl‐3‐thiosemicarbazone) (H2gtsp) is a [3+3] trinuclear triangular prism. Recrystallization of this complex in the presence of either CO2, CS2, or CH3CN leads to the formation of [4+4] open‐ended charge‐neutral tetranuclear coordination nanotubes, approximately 2 nm in length and with internal dimensions large enough to accommodate linear guest molecules, which serve to template their formation. Upon removal of the templating molecules the nanotubes demonstrated reversible sorption of CO2 with an isosteric enthalpy of sorption of 28 kJ mol−1 at low loading.
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    Synthesis of Homochiral Co-III- and Mn-IV-[2.2]Paracyclophane Schiff Base Complexes with Predetermined Chirality at the Metal Centre
    Loits, D ; Braese, S ; North, AJ ; White, JM ; Donnelly, PS ; Rizzacasa, MA (WILEY-V C H VERLAG GMBH, 2016-08-01)
    The planar chiral Schiff base ligand 2, derived from (Rp)‐5‐formyl‐4‐hydroxy‐[2.2]paracyclophane (FHPC) (1), was utilised to form a Λ‐CoIII cis‐β‐octahedral metal complex 3 with complete control of the metal‐centred chirality. In addition, a di‐µ‐oxo Λ,Λ‐MnIV complex 4 was synthesised with control of both metal‐centred and (P)‐helical chirality.
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    A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention
    Zia, NA ; Cullinane, C ; Van Zuylekom, JK ; Waldeck, K ; McInnes, LE ; Buncic, G ; Haskali, MB ; Roselt, PD ; Hicks, RJ ; Donnelly, PS (WILEY-V C H VERLAG GMBH, 2019-10-14)
    Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.
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    A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper‐64 with High Tumor Uptake and Retention
    Zia, NA ; Cullinane, C ; Van Zuylekom, JK ; Waldeck, K ; McInnes, LE ; Buncic, G ; Haskali, MB ; Roselt, PD ; Hicks, RJ ; Donnelly, PS (Wiley, 2019-10-14)
    Abstract Molecules containing lysine‐ureido‐glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine‐ureido‐glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron‐emitting copper‐64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper‐67 variant.
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    Rhenium and technetium complexes of thioamide derivatives of pyridylhydrazine that bind to amyloid-β plaques
    Fletcher, SP ; Noor, A ; Hickey, JL ; McLean, CA ; White, JM ; Donnelly, PS (SPRINGER, 2018-10)
    Age-associated deposition of amyloid-β in cerebral blood vessels, a condition referred to as cerebral amyloid angiopathy, can contribute to stroke and dementia. This research aimed to design new radioactive technetium-99 m complexes that bind to amyloid-β plaques that have the potential to assist in diagnosis of cerebral amyloid angiopathy using single-photon-emitted computed tomography (SPECT) imaging. Six new pyridylthiosemicarbazide ligands containing either benzofuran or styrylpyridyl functional groups that are known to selectively bind to amyloid plaques were prepared. Non-radioactive isotopes of technetium are not available so rhenium was used as a surrogate for exploratory chemistry. The new ligands were used to prepare well-defined [Re-oxo]3+ complexes where two pyridylthiosemicarbazide ligands were coordinated to a single metal ion to give bivalent complexes with two amyloid-β targeting functional groups. The interaction of the [Re-oxo]3+ complexes with synthetic amyloid-β1-42 and with amyloid plaques in human brain tissue was investigated. Two ligands were selected to develop methods to prepare their [99mTc-oxo]3+ complexes at the tracer level. These technetium-99 m complexes are likely to be isostructural to their rhenium-oxo analogues.
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    The social defeat/overcrowding murine psychosocial stress model results in a pharmacologically reversible body weight gain but not depression - related behaviours
    Keenan, RJ ; Chan, J ; Donnelly, PS ; Barnham, KJ ; Jacobson, LH (ELSEVIER SCIENCE INC, 2018-11)
    Depression is a highly prevalent psychiatric disorder, yet its etiology is not well understood. The validation of animal models is therefore a critical step towards advancing knowledge about the neurobiology of depression. Psychosocial stress has been promoted as a prospective animal model of depression, however, different protocols exist with variable responses, and further investigations are therefore required. We aimed to characterise the behavioural and body weight responses to the social defeat/overcrowding (SD/OC) model and to explore the effects of the antidepressant fluoxetine and the peroxynitrite scavenger, CuII(atsm), therein. Male C57BL/6JArc mice were exposed to a 19 day SD/OC protocol at two levels of aggression, determined by terminating SD bouts after one, or approximately five social defeat postures. This was followed by a battery of behavioural tests including social interaction test (SIT), locomotor activity (LMA), light-dark box test (LDB), saccharin preference test (SPT) and the forced swim test (FST). Mice were dosed daily with vehicle, fluoxetine (20 mg/kg) or CuII(atsm) (30 mg/kg) throughout the protocol. SD/OC increased body weight compared to controls, which was abolished by fluoxetine and attenuated by CuII(atsm). Weight gain specifically peaked during OC sessions but was not affected by either drug treatment. Fluoxetine reduced the number of defeat postures during fight bouts on some days. SD/OC otherwise failed to elicit depression- or anxiety-like behaviour in the tests measured. These data raise questions over the SD/OC model as an etiological model of depression-related behaviours but highlight the potential of this model for investigations into mechanisms regulating binge eating and weight gain under conditions of chronic social stress.