研究领域
Inorganic Therapeutics and Magnetic Resonance Spectroscopy
1) Mechanisms and biological interactions of ruthenium anticancer compounds
We are studying the in vitro and in vivo behaviour of Ru(III) chemotherapeutics and their mechanisms of action. Recently, we have shown the importance of serum-protein interactions to the speciation of these compounds, which lead to the maintenance of their Ru(III) oxidation state and influence aquation and oligomerization processes.
2) Design and synthesis of new metal-based anticancer drugs targeting specific biomolecule interactions
We are using ligand design to develop new Ru complexes which target hydrophobic protein binding. Hydrophobic interactions of Ru complexes with human serum albumin are a current area of focus. Ultimately, we are seeking to develop metallodrug-protein conjugates as selective anticancer agents.
3) Development of redox-activated metal-based anticancer compounds for tumour targeting
The combination of redox-active metal centres with redox-active ligands promises to produce new anticancer drug candidates which can generate ligand radicals and reactive oxygen species, while also interacting with DNA. We are developing complexes of several metal ions, which are activated in hypoxic tumour environments for targeted anticancer activity.
4) Application of EPR spectroscopy to the mechanisms of paramagnetic metallodrug candidates
Electron paramagnetic resonance (EPR) spectroscopy provides unique insight into the structure and chemical properties of paramagnetic species. We are using EPR to study the mechanisms of paramagnetic anticancer metallodrugs, such as those containing Ru(III). Using this technique we can characterize interactions with proteins, DNA, and components of serum and whole cells. We are also using EPR to determine the production of reactive oxygen species from redox-active metal complexes.
5) Structure and Reactivity of paramagnetic species, such as radicals, spin traps, reactive oxygen species
The SFU EPR/ENDOR facility enables studies of a wide array paramagnetic species. To date, this has included:
Radical reactions
Paramagnetic organometallic compounds
Redox-active metal complexes
Spin trapping of reactive intermediates
Spectroelectrochemistry
近期论文
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Prosser, K. E.; and Walsby, C. J. "Electron Paramagnetic Resonance as a Tool for Studying the Mechanisms of Paramagnetic Anticancer Metallodrugs", Eur. J. Inorg. Chem., 2017, published online.
Stott, L.A.; Prosser, K.E.; Berdichevsky, E.K.; Walsby, C. J.; and Warren, J. J. "Lowering Water Oxidation Overpotentials Using the Ionisable Imidazole of Copper(2-(2'-pyridyl)imidazole)", Chem. Comm., 2017, 53, 651-654.
Prosser, K. E.; Chang, S. W.; Saraci, F.; Le, P. H.; and Walsby C. J. "Anticancer Copper Pyridine Benzimidazole Complexes: ROS Generation, Biomolecule Interactions, and Cytotoxicity", J. Inorg. Biochem., 2017, 167, 89-99.
Zhao, J.; Prosser, K. E.; Chang S. W.; Zakharia, S.; and Walsby, C. J. "Combining a Ru(II)-Arene Complex with a NO-Releasing Nitrate-Ester Ligand Generates Cytotoxic Activity", Dalton Trans., 2016, 45, 18079-18083.
Chang, S. W.; Lewis, A. R.; Prosser,K. E.; Thompson, J. R.; Gladkikh, M; Bally, M. B.; Warren, J. J.; and Walsby, C. J. "CF3 Derivatives of the Anticancer Ru(III) Complexes KP1019, NKP-1339, and Their Imidazole and Pyridine Analogues Show Enhanced Lipophilicity, Albumin Interactions, and Cytotoxicity", Inorg. Chem., 2016, 55(10), 4850-4863.
Lemaire, M.; Walsby, C. J.; Bonanno, N. M.; Lough, A.; Prosser, K. E.; Poddutoori, P. K. "A Stable Open-shell Active Ditopic Ligand", Dalton Trans., 2016, 45(13), 5460-5463.
Mu, C.; Chang, S. W.; Prosser, K. E; Leung, A. W. Y.; Santacruz, S; Jang, T.; Thompson, J. R.; Yapp, D. T. T.; Warren, J. J.; Bally, M. B.; Beischlag, T. V.; and Walsby, C. J. "Induction of Cytotoxicity in Pyridine Analogues of the Antimetastatic Ru(III) Complex NAMI-A by Ferrocene Functionalization", Inorg. Chem., 2016, 55(1), 177-190.
Webb, M. I.; Walsby C. J. "Albumin binding and ligand-exchange processes of the Ru(III) anticancer agent NAMI-A and its bis-DMSO analogue determined by ENDOR spectroscopy", Dalton Trans. 2015, 44(40), 17482-17493.
Jones, M. R.; Mu, C.; Wang, M. C. P.; Webb, M. I.; Walsby, C. J.; Storr, T. "Modulation of the Aβ peptide aggregation pathway by KP1019 limits Aβ-associated neurotoxicity", Metallomics, 2015, 7(1), 129-135.
Makins, C.; Whitelaw, D. A.; Mu, C.; Walsby, C. J.; Wolthers, K. R. "Isotope Effects for Deuterium Transfer and Mutagenesis of Tyr187 Provide Insight into Controlled Radical Chemistry and Adenosylcobalamin-Dependent Ornithine 4,5-Aminomutase", Biochemistry, 2014, 53(33), 5432-5443.
Suet, L. Y; Säbel; C. E.; Webb, M. I; Walsby, C. J.; Siemann, S. "High Metal Substitution Tolerance of Anthrax Lethal Factor and Characterization of its Active Copper-substituted Analogue", J. Inorg. Biochem., 2014, 140, 12-20.
Mu, C. and Walsby, C. J. "Ruthenium Anticancer Compounds with Biologically-Derived Ligands", in Ligand Design in Medicinal Inorganic Chemistry, Wiley VCH, 2014, 405-437.
Webb, M. I.; Wu, B.; Jang, T.; Chard, R. A.; Wong, E. W. Y.; Wong, M. Q.; Yapp, D. T. T. and Walsby C. J. , "Increasing the Bioavailability of RuIIIAnticancer Complexes through Hydrophobic Albumin Interactions", Chem. Eur. J., 2013, 19(50), 17031-17042.
Webb, M. I. and Walsby, C. J. ,"EPR as a probe of the intracellular speciation of ruthenium(III) anticancer compounds", Metallomics, 2013, 5(12), 1624-1633.
Wong, E. W. Y.; Miura, A.; Wright, M. D.; He, Q.; Walsby, C. J.; Shimizu, S.; Kobayashi, N.; Leznoff, D. B., "Gold Phthalocyanine Revisited: Synthesis and Spectroscopic Properties of Gold (III) Phthalocyanine and an Unprecedented Ring-Contracted Phthalocyanine Analogue", Chem. Eur. J., 2012, 18(39), 12404-12410.
Simmons, J. M.; Yildirim,T; Hamaed,A; Antonelli,D. M.; Webb, M. I.; Walsby, C. J., "Direct Observation of Activated Hydrogen Binding to a Supported Organometallic Compound at Room Temperature", Chem. Eur. J., 2012, 18(14), 4170-4173.
Webb, M. I.; Chard, R. A.; Al-Jobory, Y. M.; Jones, M. R.; Wong, E. Y. W.; Walsby, C. J., Pyridine Analogues of the Antimetastatic Ru(III) Complex NAMI-A Targeting Non-Covalent Interactions with Albumin, Inorg. Chem., 2012, 51(2), 954-966.
Sherren, C. N.; Mu,C.; Webb, M. I.; McKenzie, I.; McCollum, B. M.; Brodovitch, J.-C.; Percival, P. W.; Storr, T.; Seddon, K. R.; Clyburne, J. A. C; Walsby, C. J. , "Merging the chemistry of electron-rich olefins with imidazolium ionic liquids: radicals and hydrogen-atom adducts", Chem. Sci., 2011, 2, 2173-2177.
Webb M. I.; Walsby C. J., "Control of Ligand-exchange Processes and the Oxidation State of the Antimetastatic Ru(III) Complex NAMI-A by Interactions with Human Serum Albumin", Dalton Trans., 2011, 40, 1322-1331.
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