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  • (2006) Hitchins, Megan; Suter, C; Wong, Jenny; Cheong, Kay; Hawkins, Nicholas; Leggett, B; Scott, R; Spigelman, Allan; Tomlinson, Ian; Martin, David; Ward, Robyn
    Journal Article

  • (2007) Garner, James; Harding, Margaret
    Journal Article
    The á-helix is the most abundant secondary structural element in proteins and is an important structural domain for mediating protein-protein and protein-nucleic acid interactions. Strategies for the rational design and synthesis of á-helix mimetics have not matured as well as other secondary structure mimetics such as strands and turns. This perspective will focus on developments in the design, synthesis and applications of á-helices and mimetics, particularly in the last 5 years. Examples where synthetic compounds have delivered promising biological results will be highlighted as well as opportunities for the design of mimetics of the type I á-helical antifreeze proteins. © The Royal Society of Chemistry.

  • (2007) Abeysinghe, Priyanthi; Harding, Margaret
    Journal Article
    This Perspective will focus on recent developments in the field of antitumour metallocenes structurally related to titanocene dichloride. Despite extensive testing of titanocene dichloride which culminated in phase I and II clinical trials, further trials have been abandoned. While DNA has been implicated as the major target related to anticancer activity, identification of the active species and mechanism of action has been poorly understood and hence the design of second generation titanocene derivatives has not been possible. Recent mechanistic studies have provided a plausible mechanism for delivery of Ti to cancer cells via transferrin mediated endocytosis. This mechanism requires the presence of labile Cp-Ti bonds that hydrolyse on a time scale to deliver Ti to transferrin. A large range of titanocene derivatives in which the cyclopentadienyl rings have been substituted by both electron withdrawing and donating groups, including aromatic, alkyl and cyclic amines, have been prepared and tested for activity in the last 5 years. These results have shown that subtle structural effects can have a significant effect on biological activity and that biological activity is highly cell line dependent. However, the biological chemistry and cellular studies required to determine the mechanism of action of these new titanocenes have not been reported. In contrast, the bioorganometallic chemistry and cellular studies of molybdocene dichloride have implicated interaction with cellular thiols as the key reaction related to biological activity. Tailoring of the pseudohalide ligands by tuning the strength of the Mo-S bonds provides the opportunity to enhance cell uptake. Further research is required to establish the origin of antitumour activity. © The Royal Society of Chemistry.

  • (2007) Harding, Margaret; Campbell, Kate; Dillon, Carolyn; Smith, S
    Journal Article
    Neutron irradiation Of Cp2MoCl2 for 24 h afforded the radiotracer (CP2MoCl2)-Mo-99 which was characterised by UV-Vis spectroscopy and thin layer chromatography. Binding experiments with the thiol containing protein human serum albumin (HSA) or calf thymus DNA, were monitored for Mo-99 using a gamma counter. Under the conditions investigated, molar ratios of binding of 0.2:1 (Cp2MoCl2:DNA) and 9.4:1 (Cp2MoCl2:HSA) were calculated. The results are consistent with in vitro coordination studies that have shown strong preferential interaction Of Cp2MoCl2 with thiols versus other donor sites in biomolecules including DNA. (c) 2006 Elsevier Ltd. All rights reserved.

  • (2006) Dillon, Carolyn; Harding, Margaret; Campbell, Kate; Foster, Amalanie
    Journal Article
    The cytotoxic effects of molybdocene dichloride (Cp2MoCl2) were investigated in V79 Chinese hamster lung cells using the micronucleus assay. Cp2MoCl2 produced significant genotoxic damage whereby 0.2 micronuclei/1000 binucleated cells were induced per μM of Cp2MoCl2. Transmission electron microscopic analysis of thin-sectioned cells treated with Cp2MoCl2 (300 μM) showed distinct morphological alterations of the nuclei, condensation of chromatin, and a high incidence of polynucleated cells. Implications for the mechanism of antitumor action of molybdocene dichloride are discussed.

  • (2006) Inglis, Steven; Turner, J; Harding, Margaret
    Journal Article
    Antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs), found in the body fluids of many species of polar fish allow them to survive in waters colder than the equilibrium freezing point of their blood and other internal fluids. Despite their structural diversity, all AF(G)Ps kinetically depress the temperature at which ice grows in a noncolligative manner and hence exhibit thermal hysteresis. AF(G)Ps also share the ability to interact with and protect mammalian cells and tissues from hypothermic damage (e.g., improved storage of human blood platelets at low temperatures), and are able to stabilize or disrupt membrane composition during low temperature and freezing stress (e.g., cryoprotectant properties in stabilization of sperm and oocytes). This review will summarize studies of AFPs with phospholipids and plant lipids, proposed mechanisms for inhibition of leakage from membranes, and cryoprotectant studies with biological samples. The major focus will be on the alpha-helical type I antifreeze proteins, and synthetic mutants, that have been most widely studied. For completeness, data on glycoproteins will also be presented. While a number of models to explain stabilization and destabilization of different lipid systems have been proposed, it is currently not possible to predict whether a particular AFP will stabilize or destabilize a given lipid system. Furthermore the relationship between the antifreeze property of thermal hysteresis and membrane stabilization is unknown. This lack of detailed knowledge about how AFPs function in the presence of different types of materials has hampered progress toward the development of antifreezes for cold storage of cells, tissues, and organs.

  • (2006) Rendina, L; Harding, Margaret; Lee, Chun-Cheng; Groneman, J; Turner, Peter
    Journal Article
    Ditopic symmetrical bis(pyridyl) ligands incorporating the chiral dibenzobicyclo[b,f][3.3.1]nona-5a,6a-dieiie-6,12-dione cleft have been synthesised and characterised by NMR spectroscopy, mass spectrometry and X-ray crystallography. The ligands, which incorporate pyridyl groups directly connected to the carbocyclic cleft core or via alkyne or phenyl linkers were accessed from palladium-catalysed coupling reactions of 2,8-dibromodibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione. X-ray crystal analyses show the interplanar angles between the two cleft aromatic rings in these molecules, which range from 97.80(3) to 109.80(4)degrees. (c) 2006 Elsevier Ltd. All rights reserved.

  • (2006) Waern, J; Turner, P; Harding, Margaret
    Journal Article
    Hydrolysis studies of derivatives of molybdocene dichloride in which the two chloride ligands were replaced by 3,5-bis(trifluoromethyl)thiophenol, 3,5-bis(trifluoromethyl)benzyl thiol, and 2,2,2-trifluoro-ethane thiol ligands confirmed that the electron-withdrawing groups affect the lability of the Mo-S bonds and promote slow generation of the putative biologically active species `Cp2Mo2+`; the trifluoroethane thiol derivative underwent 50% hydrolysis in 14 h in 10% D2O/DMSO-d6. The structure of molybdocene bis(S-3,5-bis(trifluoromethyl)benzyl thiol) was confirmed by X-ray crystal structure analysis. © 2006 American Chemical Society.

  • (2006) Price, W; Harding, Margaret; Inglis, Steven; McGann, M
    Journal Article
    Pulsed field gradient spin echo NMR spectroscopy was used to measure diffusion coefficients of the alpha-helical type I antifreeze protein from the winter flounder, two synthetic derivatives in which the four Thr residues were replaced with Val and Ala, respectively, and the low molecular weight fraction antifreeze glycoprotein. Under the conditions studied, the natural type I antifreeze protein and low molecular weight glycoprotein gave diffusion values that were consistent with the presence of monomeric protein in solution. While significant aggregation of the Ala analogue was observed (2-10 mM), there was no evidence for aggregation in the Val analogue (1-3 mM). These results are compared with previously reported solubility and thermal hysteresis data and the implications for the design of synthetic antifreeze proteins are discussed. (c) 2006 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  • (2006) Tarnopolsky, Alex Z.; Fletcher, Neville H.; Hollenberg, Lloyd C. L.; Lange, Benjamin D.; Smith, John; Wolfe, Joseph
    Journal Article
    The didjeridu, or yidaki, is a simple tube about 1.5 m long, played with the lips, as in a tuba, but mostly producing just a tonal, rhythmic drone sound. The acoustic impedance spectra of performers' vocal tracts were measured while they played and compared with the radiated sound spectra. When the tongue is close to the hard palate, the vocal tract impedance has several maxima in the range 1-3 kHz. These maxima, if sufficiently large, produce minima in the spectral envelope of the sound because the corresponding frequency components of acoustic current in the flow entering the instrument are small. In the ranges between the impedance maxima, the lower impedance of the tract allows relatively large acoustic current components that correspond to strong formants in the radiated sound. Broad, weak formants can also be observed when groups of even or odd harmonics coincide with bore resonances. Schlieren photographs of the jet entering the instrument and high speed video images of the player's lips show that the lips are closed for about half of each cycle, thus generating high levels of upper harmonics of the lip frequency. Examples of the spectra of 'circular breathing' and combined playing and vocalization are shown.