Chris Orvig

Prospective Graduate Students / Postdocs

This faculty member is currently not actively recruiting graduate students or Postdoctoral Fellows, but might consider co-supervision together with another faculty member.


Research Classification

Research Interests

Chemical Synthesis and Catalysis
Inorganic and Organometallic Compounds
Nuclear medicine
Chemical Processes
bioinorganic chemistry
coordination chemistry
ligand design and synthesis
medicinal inorganic chemistry
radiopharmaceutical chemistry

Relevant Degree Programs

Affiliations to Research Centres, Institutes & Clusters



Chris Orvig was born in Montréal in 1954 and educated in that city, following his father to McGill University to obtain his First Class Honors BSc in Chemistry in 1976. He then studied with Professor Alan Davison, FRS at the Massachusetts Institute of Technology as a Natural Sciences and Engineering Research Council (NSERC) of Canada Postgraduate Scholar (PGS), obtaining his PhD in 1981. After two years at the University of California, Berkeley as an NSERC Postdoctoral Fellow (PDF) with Prof. K. N. Raymond, and an additional year at McMaster University with Prof. C. J. L. Lock, he joined the Chemistry Department at UBC in 1984 as an NSERC University Research Fellow. At UBC, he was appointed Assistant Professor in 1988, Associate Professor in 1990, Associate Member of the Faculty of Pharmaceutical Sciences in 1991, Director of the Medicinal Inorganic Chemistry Group in 1994 and Professor of Chemistry in 1995. He was acting Head of Chemistry in 2000-2001 and Associate Head of Chemistry in 2010-11.
Orvig is one of the world’s foremost experts in medicinal inorganic chemistry. His earliest independent work showed that low-molecular-weight aluminum compounds of neutral charge and considerable aqueous solubility over a wide pH range could be prepared; this has led to the wide and on-going use of this compound to study aluminum toxicity and pharmacology. His radiopharmaceutical research projects have discovered agents to investigate the imaging of heart, kidney, brain, and certain tumours; he has also been working recently on a versatile modular chelating system for both therapeutic and diagnostic applications of radiometal ions. In the 1990s, he published an extensive and comprehensive series of papers on the discrimination of multidentate ligands for different metal ions of biological importance and he has pursued trifunctional agents for the treatment of Alzheimer’s disease. His research in collaboration with Professor John McNeill, FRSC (formerly UBC Dean of Pharmaceutical Sciences) elucidated vanadium compounds as non-toxic, orally active analogues of insulin in the treatment of diabetes mellitus. The impact of Orvig's vanadium drugs for diabetes treatment is indicated by the completion of phase 2 clinical trials in type 2 diabetics in May 2008.
At the invitation of the American Chemical Society, he edited the September 1999 Chemical Reviews special issue on Medicinal Inorganic Chemistry, the first comprehensive treatise in this field, and he was invited by Science to review the field in 2003. He serves on many editorial and institutional boards (chairing that for Dalton Transactions 2008-2011), and was the inorganic chemistry editor of the Canadian Journal of Chemistry for ten years. Orvig has been an invited/plenary speaker hundreds of times at national and international meetings; his research expertise is regularly sought by companies as a consultant. In the early 1990s, he acted as a crucial expert witness in a seminal lawsuit in the USA that won compensation for neurological damage in aluminum smelter workers.
Orvig chaired the 31st International Conference on Coordination Chemistry (ICCC) at UBC in 1996, the 2004 Metals in Medicine Gordon Research Conference, and the 15th International Conference on Biological Inorganic Chemistry (ICBIC) at UBC in 2011. He is now the Executive Secretary for the ICCC.
Orvig’s research has been recognized by receipt of an Alexander von Humboldt Research Prize (Germany), a Japan Society for the Promotion of Science (JSPS) Invitation Fellowship, and UBC Killam Awards for research and teaching. In 2009, he received both the Rio Tinto Alcan Award, for inorganic or electrochemistry, from the Canadian Society for Chemistry, and the Bioinorganic Chemistry Award from the Royal Society of Chemistry. He was elected Fellow of the Royal Society of Canada in 2010, and served as Davison Lecturer at MIT in 2011 and G. Ronald Brown Lecturer at McGill in 2014. He won a Canada Council for the Arts Killam Research Fellowship for 2011-2013, and UBC’s highest research honour, the Jacob Biely Research Prize, in 2013. Recently, the Alexander von Humboldt Foundation named him Humboldt Ambassador Scientist for 2015-2021.

Graduate Student Supervision

Doctoral Student Supervision

Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.

Development of metal-based (radio)pharmaceuticals for imaging and therapy (2021)

Contemporary metalloradiopharmaceuticals are usually comprised of four components; radionuclide, bifunctional chelator, linker and targeting vector. Physical decay of the radionuclide is responsible for the diagnostic or therapeutic effect of the drug, and the bifunctional chelator simultaneously binds the radiometal ion to prevent release in vivo and provides a handle for covalent linkage to the other component of the molecule. Optimal performance of these components is essential for effective radiopharmaceuticals, and have been the focus of this thesis. Antimony-119 is considered one of the most promising radionuclides for Auger electron therapy; however, few studies exploring separation and radiolabeling of radioantimony exist in the literature. Bombardment of natSn with 12.8 MeV protons achieved production of primarily ¹²⁰mSb, as well as ¹¹⁷mSn. These species were then used to monitor separation radiochemistry and the purified ¹²⁰mSb was successfully radiolabeled. Non-bifunctional chelators H₆phospa, H₆dipedpa, and H₆eppy were synthesized and studied with In³⁺, Lu³⁺, Y³⁺, Sc³⁺, and La³⁺ via NMR and thermodynamic solution studies. Results showed that H₆phospa formed the most thermodynamically stable complexes. As a result, H₆dappa was synthesized as a bifunctional analogue. While thermodynamic results were encouraging, serum stability studies revealed complex lability, which was further supported by DFT calculations. Inspired by interest in [²⁰³/²¹²Pb]Pb²⁺, DTPAm was synthesized and studied. NMR spectra and preliminary radiolabeling studies with [²⁰³Pb]Pb²⁺ were encouraging; however, thermodynamic parameters and serum stability studies (with ²⁰³Pb) pointed towards complex lability, likely as a result of the lack of ionisable protons of DTPAm. Lastly, interest in phosphonate-bearing ligands resulted in studies exploring their use in delivering oral La³⁺ for bone-resorption disorders. Working closely with Dr. David Weekes, large scale batches of La(XT) were synthesized. Following animal studies, the lanthanum content of animal tissue (healthy Sprague Dawley rats) was analyzed by ICP-MS. Short-term studies (4 weeks) pointed towards dose-dependent lanthanum concentrations in bone (femur) and no observable toxicity. Long-term studies (3 months) showed no kidney or liver toxicity, however minimal mechanical advantage of La³⁺ incorporation into bone was noted. Synthesis and NMR studies were also carried out on dppa and DEDA-(PO) to investigate their stability with La³⁺, among other metal ions.

View record

Non-macrocyclic chelators for metal-based radiopharmaceuticals (2021)

Radiometals have unique decay properties and half-lives. In order to harness their valuable properties for use in medicine, we need chelators to tightly bind them and transport them to the desired site in vivo for imaging or therapy. The macrocyclic chelators used in the clinic suffer from poor metal coordination match and exhibit slower kinetics, while the non-macrocyclic chelators are known for their faster complexation times under ambient conditions and are compatible for conjugation to antibodies for specific targeting. This thesis describes the design, synthesis and evaluation of non-macrocyclic chelators for radiometals. The coordination chemistry of metal complexes has been studied by solid-state crystal structure analysis, NMR spectroscopy, combined potentiometric and UV-Vis spectrophotometric titrations, and DFT calculations to study their aqueous chemistry. Radiolabeling studies and transchelation studies against human serum proteins were conducted to evaluate their use in radiopharmaceuticals. Bispidine-based H₂bixpox² was synthesized and the metal complexes with In³⁺ and Lu³⁺ were characterized by X-ray single-crystal structure and NMR spectroscopy. Radiolabeling experiments revealed high radiolabeling efficacy of H₂bispox² with [¹¹¹In]In³⁺ and [¹⁷⁷Lu]Lu³⁺. H₃glyox, a hexadentate chelator was synthesized and was found to form thermodynamically stable neutral complexes with three major radiometal ions ([⁴⁴Sc]Sc³⁺, [⁶⁸Ga]Ga³⁺ and [¹¹¹In]In³⁺); the pM values follow the order: pIn (34.0) > pSc (26.0) > pCu (25.2) > pGa (24.9) > pLu (18.1) > pMn (12.0). Quantitative radiolabeling with [⁶⁸Ga]Ga³⁺ (RCY > 95%, [L] = 10-5 M) and [¹¹¹In]In³⁺ (RCY > 99%, [L] = 10⁻⁸ M) was achieved under ambient conditions (RT, pH 7 and 15 min) with very high apparent molar activities of 750 MBq/μmol and 650 MBq/nmol, respectively. The chelation enhanced fluorescence of the natSc(glyox) and natGa(glyox) complexes was used to investigate their cellular distribution in the live HeLa cells. Preliminary studies were done to access the use of [Mn(glyox)]⁻ complex for 52/55Mn-based bimodal PET/MRI imaging and the results were promising. Lastly, a preorganized octadentate chelator, H₄HBEDpa was designed and synthesized, which forms highly thermodynamically stable complexes with trivalent metal ions. Competition experiments against excess apo-transferrin revealed high resistance of the [Fe(HBEDpa)]⁻ complex (logKFeL = 36.62) to transchelation even after 7 days.

View record

Metal chelating agents for medicinal radionuclides (2020)

Medical radionuclides can be classified into non-metallic and metallic. Due to the much broader decay spectrum, radiometal ions are generally of greater interest in radiopharmaceutical designs. Since free radionuclides are rapidly taken up by the non-targeting organs/tissues such as bone, liver and kidney, causing unnecessary radiation burden to the body, they need to be stably coordinated by a suitable bifunctional chelator conjugated to a biological targeting vector, which directs the radiation doses specifically to the tumor site. This thesis describes several picolinate-based ligand scaffolds (H4octapa, H4pypa and H4py4pa) with denticity from eight to eleven to accommodate radionuclides as small as scandium-44 and as large as actinium-225. Apart from rapid and stable chelation, versatile bifunctionalization is a crucial but often under-valued property of a ligand. The chemical properties of the linker can significantly alter the biodistribution of the chelate-bioconjugate, while the position of the linker in the ligand can dictate the coordination geometry. The second effect was observed in two newly developed 177Lu-labeled H4octapa peptide conjugates discussed in this thesis. This observation prompted the development of two functionally versatile chelators, H4pypa and H4py4pa, with increased rigidity imposed by the central pyridyl moiety that connects the pendent chelating arms. The central pyridyl moiety also serve as a convenient and robust bioconjugation spot. Studies of H4pypa with scandium-44, lutetium-177, indium-111, yttrium-86, zirconium-89, and H4py4pa with actinium-225 were conducted, while their biological properties were evaluated with either the peptide- or the antibody-conjugates, showing favorable radiolabeling results and stability which even surpassed the current “gold-standard” chelator, DOTA, rendering them highly promising for the applications in nuclear medicine.

View record

New chelators for radiopharmaceutical chemistry (2019)

This thesis presents studies on a new family of oxine (8-hydroxyquinoline) based acyclic chelators for application to radiometals (e.g., ⁶⁴Cu, ⁶⁷/⁶⁸Ga, ¹¹¹In) in nuclear medicine. Picolinic acid-based chelators (“pa” family) are reported as excellent radiometal chelators by our group’s previous study. Further development leads to the next generation chelators – the “ox” family (8-hydroxyquinoline). H₂hox showed a marked improvement from its “pa” counterpart, H₂dedpa, including an easy preparation, single complex species in a broad pH range (1-11) and high log KML (34.4) and pM (28.3) values. H₂hox showed fast (5 minutes) and quantitative ⁶⁸Ga labelling at room temperature with a concentration as low as 10-⁷ M and obtained a high molar activity. Excellent in vitro and in vivo stability was confirmed with plasma challenge experiments and dynamic PET imaging. The chelation enhanced fluorescence emission property was used directly to investigate the cellular distribution of [Ga(hox)]⁺ and showed the potential for dual channel imaging. Expanding from the lead chelator, H₂CHXhox was then synthesized by incorporating a cyclohexane (CHX) in the backbone to pre-organise the chelator and showed a great improvement on the kinetic inertness and thermodynamic stability. H₂C3hox was prepared by adding one more carbon to the backbone of H₂hox to obtain a 6-membered chelate ring, in order to investigate the preference of ring size on metal ion radii. H₂C3hox showed a decrease in solution stability, thought to be due to adopting a less stable conformation in the 6-membered chelate ring. H₄octox was designed with increased denticity (N₄O₄) vs H₂hox (N₄O₂) for larger metal ions and showed fast and stable chelation with metal ions (Y³⁺, In³⁺, La³⁺, Lu³⁺and Gd³⁺) in solution. Its in vitro stability with In³⁺ and Y³⁺ was proved using plasma and Fe³⁺ challenge experiments, and in vivo stability was confirmed with ¹¹¹In SPECT imaging. The 60-fold fluorescence emission increase when complexed with Y³⁺ can also be applied in probe design or bi-modal imaging. These studies have indicated that the new “ox” family of chelators is an excellent and useful platform in the development of radiometal-based pharmaceuticals.

View record

Metallodrugs for therapy and imaging: investigation of their mechanism of action (2018)

In this thesis, the application of metallodrugs for therapy and imaging was investigated as part of the field ofmedicinal inorganic chemistry. In the introduction, an overview was given on the application of organic molecules,incorporating a metal or radiometal for either therapeutic or diagnostic purposes, particularly in relation to cancer. It isevident that their mechanism of action, their pharmacokinetic behaviour and biological targets are mostly not fullyelucidated yet. Thus, our overall aims included: i) to synthesize new radiopharmaceuticals for either cancer therapy orimaging, and ii) to elucidate the mechanism of cellular uptake and excretion, the anti-cancer activity and the organtoxicity of some new Au containing metallodrugs in comparison to cisplatin. To investigate the toxicity and transportmechanisms of the new cytotoxic organometallic Au(III) compounds, the ex vivo model of precision cut tissue slicesand human cell cultures in vitro were used.The work described in Part A was performed at the University of British Columbia in Vancouver, BC, Canada inthe Department of Medicinal Inorganic Chemistry under the supervision of Prof. Chris Orvig. Different radiotracers weredeveloped and characterized by chemical-physical methods. Radiolabeling experiments were also performed atTRIUMF (Canada’s national laboratory for particle and nuclear physics and accelerator-based science) and in vivoanimal experiments were conducted at the BC Cancer Agency.In chapter A1, we report on the synthesis of H₄neunpa and its immunoconjugate H₄neunpa-trastuzumab(Figure 1) and showed that it can be efficiently radiolabeled with ¹¹¹In³⁺ at ambient temperature within 15 min or 30 min,respectively. ¹¹¹In is a gamma emitter and can thus be used for single photon emission computed tomography (SPECT).The immunoconjugate was further investigated in an in vivo model using HER2/neu positive subcutaneous SKOV-3ovarian cancer xenografts bearing mice. Unfortunately, our results showed an unexpected lower accumulation of 111Inneunpa-trastuzumab into the tumor compared to the gold-standard ¹¹¹In-CHX-DTPA-trastuzumab, which was supportedby Immuno-SPECT images taken after 1 day, 3 days and 5 day post injection. Consequently, ¹¹¹In-neunpa-trastuzumabdoes not seem to be suitable for clinical application, although in vitro experiments (immunoreactivity, radiolabelingefficiencies, stability in human serum) showed similar or superior properties of this chelator compared to the goldstandard.A reason for this lower accumulation might be a difference in internalization process of the chelator-HER2/neu-receptor complex. Finally, radiolabeling of H₄neunpa with ¹⁷⁷Lu, a therapeutic radiometal, was tried butappeared unsuccessful. Comparison of In³⁺ (92pm CN=8) and Lu³⁺ (103pm CN=9)¹ leads to the hypothesis that eitherLu³⁺ might be too big for H₄neunpa or the preferred coordination number is not saturated because of steric hindrance.

View record

Lanthanum Complexes as Therapeutic Agents for the Treatment of Bone Resorption Disorders (2016)

Lanthanum naturally targets and binds skeletal tissue in living systems, wherein it has the potential to treat bone resorption disorders by invoking a biological response that counteracts an imbalanced bone remodeling cycle. Because lanthanum is very poorly absorbed, the key to realizing this potential is through rational chelator design, and in this regard, a number of lanthanum complexes have been designed, synthesized, and tested in an effort to develop an orally-active drug. Previously, past group members Dr. Cheri Barta and Dr. Yasmin Mawani had identified tris-(1,2-dimetyl-3-oxypyridin-4-one) lanthanum(III) (La(dpp)₃) and bis-[[bis(carboxymethyl)amino] methyl]phosphinate lanthanum(III) (La(XT)) as lead drug candidates, and – after tailoring the synthetic procedures to access large quantities of each – these compounds were tested for their thermodynamic and kinetic interactions with synthetic hydroxyapatite (HAP) by isothermal titration calorimetry (ITC) and solution depletion studies, respectively. The systems were also tested for the first time in vivo (healthy Sprague Dawley rats) by measuring lanthanum biodistribution from single-dose intravenous (IV), acute IV, and short-term IV and oral administration of either compound. Overall, it was found that La(XT) was a more viable candidate than La(dpp)₃, primarily due to higher thermodynamic stability which led to better oral uptake. Four new compounds (H₂dpa, H₃cedpa, H₄pedpa, and H₇alenpa) and three of their lanthanum complexes (all but H₇alenpa) were also synthesized, and tested for ligand binding kinetics with HAP (solution depletion studies), thermodynamic stability of the lanthanum complexes (potentiometric and NMR titrations), and lipophilicity of both the ligands and the metal complexes (partition coefficient measurements). It was found that [La(pedpa)]- exhibited the most favourable overall profile for a potential drug candidate, but requires further testing before in vivo trials. Crystal structures for [La₄(pedpa)₄(H₂O)₂] and [La(dpp)₃(H₂O)₂]·11.75H₂O were also obtained.

View record

Acyclic Chelating Ligands for Radiometals (2015)

This thesis presents studies on a class of acyclic (open chain) chelating ligands based on the picolinic acid moiety. Our recent reports of the promising hexadentate chelator H₂dedpa and octadentate analogue H₄octapa for Ga(III) and In(III)/Lu(III) complexation, respectively, have spurred our interest in further developing this class of chelators, which have subsequently been dubbed the “pa” family of ligands. These ligands possess the potential to bind a variety of clinically relevant radiometal ions, such as ⁶⁸Ga, ⁶⁴Cu, ¹¹¹In, ¹⁷⁷Lu, or ⁸⁶/⁹⁰Y. When harnessed properly, the radiative emissions of these radiometals can be utilised in radiopharmaceuticals for imaging (via γ-rays for single photon emission computed tomography (SPECT) or β+ particles for positron emission tomography (PET)) or therapy (via highly ionizing radiation from α, β-, or Auger electron emission). A key component of these radiometal-based radiopharmaceuticals is the chelating ligand, used to securely bind the radiometal which ensures proper delivery the radioactive dose to the area of interest in vivo. This work focuses on further exploiting the H₂dedpa (N₄O₂) and H₄octapa (N₄O₄) scaffolds that possess ideal properties for ⁶⁷/⁶⁸Ga and ¹¹¹In radiopharmaceuticals, respectively – such as mild room temperature radiolabeling in 10 min, and the ability to form kinetically inert complexes – rare manifestations for acyclic ligands. Herein, efforts were made to incorporate dedpa²- into a small molecule imaging agent for ⁶⁸Ga PET. A variety of dedpa²- (and one octapa⁴-) analogues were synthesized, characterized, and evaluated through thermodynamic stability, in vitro kinetic inertness, and radiolabeling studies to assess their “usefulness” as ligands in radiopharmaceutical design. The chiral ligands H₂CHXdedpa and H₄CHXoctapa are highlights of this work; [Ga(CHXdedpa)]+ and [In(CHXoctapa)]- were found to be more, or equally, stable versus their achiral counterparts H₂dedpa and H₄octapa. Nitroimidazole-containing H₂dedpa and H₂CHXdedpa derivatives were also studied as potential ⁶⁸Ga PET imaging agents of tumour hypoxia. The radio-tracers showed exceptional in vitro stability (86 to >99% intact), and promising preferential uptake in hypoxic cell lines suggesting these ligands would be ideal candidates for further testing in vivo.

View record

Coordination Chemistry of Antimicrobial and Anticancer Agents (2015)

The World Health Organization has named the resistance of microbes to known antimicrobial drugs as an increasingly serious threat to global public health. Isolates of the ESKAPE pathogens (E. faecium, S. aureus, K. pneumonia, A. baumanii, P. aeruginosa, and Enterobacter species) are responsible for many nosocomial infections each year that require complicated, and therefore expensive, medical treatment, often leading to death in immune-compromised patients. Over the past 50 years, (fluoro-)quinolone antimicrobial agents have been widely used in the clinic as broad-spectrum antibiotics, but lately growing resistance against this drug class has been reported. Combining metal ions with known organic small-molecule drugs is one strategy to overcome such developed resistances. Previously, the antimicrobial properties of copper(II) and gallium(III) had been investigated, leading to Greek mythology comparisons for their mechanism of action: Cu²⁺ as the ”Achilles Heel”, Ga³⁺ as the ”Trojan Horse” subterfuge for Fe³⁺. In this thesis, gallium(III) and copper(II) coordination complexes of (fluoro-)quinolone antimicrobial agents, and derivatives thereof, were synthesized in an attempt to combine the antimicrobial potency of Cu²⁺ and Ga³⁺ with that of the quinolone antimicrobial agents in one molecule. The antimicrobial susceptibility of these coordination complexes was evaluated against five isolates of the ESKAPE pathogens; combinational effects between the metals and the quinolone ligands were not observed. While the combination of metal ions with small, organic drug molecules may lead to novel potent metallodrugs, the interaction of metal ions with drugs in vivo is often associated with toxic side-effects of medical treatment, for which the iron(III)-mediated cumulative-dose cardiotoxicity of doxorubicin is one example. Vosaroxin is a first-in-class anticancer quinolone derivative in clinical trials. Unlike the anthracycline anticancer drug doxorubicin, vosaroxin is minimally metabolized in vivo. Spectrophotometric titrations and further studies of the isolated tris(vosaroxino)iron(III) and -gallium(III) complexes supported a strong coordination of the metal ion suggesting that vosaroxin treatment may not result in cardiotoxicity.

View record

Novel multifunctional ligands and their application in Alzheimer's disease (2014)

Alzheimer’s disease (AD) is a fatal, neurodegenerative disorder that is the most common cause of dementia currently affecting over 35 million people. Metal ions Cu(II), Zn(II), and Fe(III) have a dual deleterious role in Alzheimer’s disease through acceleration of aggregation that leads to increased toxicity of the amyloid protein, and participation in catalytic cycles generating reactive species. The therapeutic effect of metal chelating agents is currently explored in clinical studies, as there are currently no drugs for this disease. This thesis investigates the 3-hydroxy-4-pyridinone family of chelating ligands, with attention given to its multifunctional activities. The main goal is to demonstrate that metal and amyloid-binding functionalities are compatible within this scaffold, while other functionalities are retained. Novel chelating agents 1-(benzo[d]oxazol-2-ylmethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hmbo2p), 1-(benzo[d]thiazol-2-ylmethyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hmbt2p), 1-(2-aminobenzo[d]thiazol-6-yl)-3-hydroxy-2-methylpyridin-4(1H)-one (Habt6p), 1-(4-(benzo[d]oxazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hpbo2p), and 1-(4-(benzo[d]thiazol-2-yl)phenyl)-3-hydroxy-2-methylpyridin-4(1H)-one (Hpbt2p) were designed, synthesised, and structural characterised. The metal binding of Hmbo2p to Cu(II), Zn(II), and Fe(III) was confirmed with titration studies, while the solid state structures of Hmbt2p were characterised using X-ray crystallography. Amyloid binding functionalities of Hmbo2p were confirmed with microscopy, fluorescence, and binding studies. Moreover, the radical quenching ability of Hmbo2p was established in the absence and presence of Cu(II) by absorbance and fluorescence studies. As well, compounds Hmbo2p, Hmbt2p, and Habt6p were found to be relatively toxic in a mouse endothelial neuronal cell line, while Hpbt2p was visualised to permeate into the cell line. Finally, by installing a carbamoyl functionality, novel compounds 2-methyl-4-oxo-1-phenyl-1,4-dihydropyridin-3-yl dimethylcarbamate (Cppp), 4-(3-hydroxy-2-methyl-4-oxopyridin-1(4H)-yl)phenyl dimethylcarbamate (Chpp), and 4-(((2-methyl-4-oxo-1-phenyl-1,4-dihydropyridin-3-yl)oxy)methyl)phenyl dimethylcarbamate (Cbppp) were synthesised for the purpose of adding an acetylcholinesterase (AChE) inhibitory functionality. The metal chelation site was masked on Cppp and Cbppp; all three inhibited eelAChE reversibly in vitro. The work presented herein demonstrates for the first time that incorporation of benzoxazole group into the hydroxypyridinone scaffold imbues it with amyloid-binding functionality while retaining the metal chelating ability. This insertion and concomitant increase of lipophilicity leads to morphological changes of amyloid protein upon incubation, and potentially results in increased toxicity and cell permeability. Finally, masking the hydroxyl group with a carbamate functionality on the scaffold leads to generation of reversible enzyme inhibitors.

View record

Synthesis, evaluation, and application of new ligands for radiometal based radiopharmaceuticals (2014)

Radiometals comprise many useful radioactive isotopes of various metallic elements. When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, e.g. ⁶⁷Ga, ⁹⁹mTc, ¹¹¹In, ¹⁷⁷Lu) and positron emission tomography (PET, e.g. ⁶⁸Ga, ⁶⁴Cu, ⁴⁴Sc, ⁸⁶Y, ⁸⁹Zr), as well as therapeutic applications (e.g. ⁴⁷Sc, ¹¹⁴mIn, ¹⁷⁷Lu, ⁹⁰Y, ²¹²/²¹³Bi, ²¹²Pb, ²²⁵Ac, ¹⁸⁶/¹⁸⁸Re). A fundamental critical component of a radiometal-based radiopharmaceutical is the ligand that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo. This thesis describes the design, synthesis, and evaluation of novel acyclic ligands based on the versatile picolinic acid moiety. Acyclic ligands have been selected because facile ambient temperature radiolabeling is an important property when working with heat sensitive molecules such as antibodies, as many currently used ligands require high temperatures for optimal radiolabling performance. Previous work in the Orvig group has determined the acyclic ligand H₂dedpa to possess ideal properties for ⁶⁷/⁶⁸Ga radiochemistry. In light of this success, this thesis has been dedicated to expansion of the H₂dedpa molecular scaffold to accommodate larger radiometals with ligand denticities ranging from 8-10. Once synthesized, new ligands are studied by standard chemical characterization, as well as potentiometric titrations to determine thermodynamic stability parameters, and radiolabeling and in vitro/in vivo stability studies of both “bare” ligands and antibody bioconjugates. The ligand H₄octapa is a highlight of this body of work, and has been found to possess excellent properties with the radiometals ¹¹¹In and ¹⁷⁷Lu, matching or in some cases surpassing the current industry “gold standard” ligand DOTA. A second highlight is the ligand H₆phospa, which is demonstrated to possess enhanced ⁸⁹Zr radiolabeling properties to H₄octapa, showing the best ⁸⁹Zr radiolabeling performance of any new ligand in several decades, with only DFO retaining superior properties.

View record

Lanthanides and their Complexes for the Treatment of Bone Density Disorders (2012)

Lanthanides are of interest in the treatment of bone density disorders because they are foundto accumulate preferentially in bone (in vivo), have a stimulatory effect on bone formation,and exhibit an inhibitory effect on bone degradation (in vitro), altering the homeostasis of thebone cycle. In an effort to develop an orally active lanthanide drug, a series of 3-hydroxy-4-pyridinone ligands were synthesized and eight of these ligands (H1 = 3-hydroxy-2-methyl-1-(2-hydroxyethyl)-4-pyridinone, H2 = 3-hydroxy-2-methyl-1-(3-hydroxypropyl)-4-pyridinone,H3 = 3-hydroxy-2-methyl-1-(4-hydroxybutyl)-4-pyridinone, H4 = 3-hydroxy-2-methyl-1-(2-hydroxypropyl)-4-pyridinone, H5 = 3-hydroxy-2-methyl-1-(1-hydroxy-3-methylbutan-2-yl)-4-pyridinone, H6 = 3-hydroxy-2-methyl-1-(1-hydroxybutan-2-yl)-4-pyridinone, H8 = 1-carboxymethyl-3-hydroxy-2-methyl-4-pyridinone, H9 = 1-carboxyethyl-3-hydroxy-2-methyl-4-pyridinone) were coordinated to ³⁺(Ln = La, Eu, Gd, Lu) formingstable tris-ligand complexes (LnL­­₃, L = 1-, 2-, 3-, 4-, 5-, 6-, 8- and 9-). The dissociation (pKan)and metal ligand stability constants (log βn) of the 3-hydroxy-4-pyridinones with La³⁺ andGd³⁺ were determined by potentiometric titrations, which demonstrated that the 3-hydroxy-4-pyridinones form stable tris-ligand complexes with the lanthanide ions. One phosphinate-EDTA derivative (H₅XT = bis[[bis(carboxymethyl)amino]methyl]phosphinate) was alsosynthesized and coordinated to Ln³⁺ (Ln = La, Eu, Lu), forming the potassium salt of[Ln(XT)]²-. Lastly, the naturally occurring curcuminoids found in turmeric were separatedinto the three naturally occurring components (HCurc = (1E,6E)-1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, HDMC = (1E,6E)-1,7-bis(4-hydroxy-3-methoxy-phenyl)hepta-1,6-diene-3,5-dione, HBDMC = (1E,6E)-1,7-bis(4-hydroxy-phenyl)hepta-1,6-diene-3,5-dione); HCurc was then coordinated to Ln³⁺ (Ln = Eu,Gd, Yb, Lu), forming Ln(Curc)­­₃ complexes. The free ligands and metal complexes werestudied for their in vitro efficacy. Cytotoxicity assays were carried out in MG-63 cells; withthe exception of the curcuminoids, all the ligands and metal complexes tested were observedto be non-toxic to this cell line. Further studies to investigate the toxicity, cellular uptake and iiiapparent permeability (Papp) of the lanthanide ions were conducted in Caco-2 cells and it was observed that [La(XT)]²- had the greatest cell uptake. Investigation into the binding affinities of free lanthanide ions (Ln = La, Gd and Lu), metal complexes and free 3-hydroxy-4-pyridinones with the bone mineral (HAP) indicate a strong binding affinity of the lanthanide ions for HAP, as well as a moderate to strong interaction of the free ligand with the bone mineral depending on the functional group.

View record

Synthesis and biological activity of chloroquine ferrocenyl conjugates for the treatment of malaria (2012)

Malaria is one of the main causes of mortality and morbidity in the world, endangeringbillions and affecting millions of people each year. Resistance to common antimalarial drugshas proven to be a challenging problem in malaria control. In an attempt to develop aneffective and affordable treatment for malaria, ferrocenyl conjugates incorporating acommon antimalarial drug such as chloroquine have been developed.Based on the previous successes of organometallic derivatives of classicalpharmacophores, a series of chloroquine-bridged ferrocenyl derivatives was synthesized.These novel compounds present an unprecedented binding mode of chloroquine to theferrocene moiety, through the bridging of the two Cp rings. The structural effects of this typeof conjugation of chloroquine and ferrocene were studied by NMR spectroscopy and crystalstructure determination.These compounds were studied along with the monosubstituted ferrocenyl analogs and theorganic components in order to compare the effects of the substitution on their biologicalresponse. The antiplasmodial activity of these sets of compounds was evaluated against thechloroquine-sensitive (D10) and the chloroquine-resistant (D2d and K1) malaria parasite(Plasmodium falciparum) strains. Additionally, their biological activity was assessed using anumber of in vitro assays. Biological and physical properties were correlated to theantimalarial activity.All compounds were active against the tested parasite strains. The presence of theferrocene significantly improved the antiplasmodial action, when compared to chloroquine,against the drug-resistant parasite strains. While the chloroquine-bridged ferrocenylderivatives were in general less active than the monosubstituted ferrocenyl analogs, they retained activity in the drug-resistant strain to a greater extent. Their particular conformation,compact size and lipophilicity/hydrophilicity balance could be providing them with thestructural characteristics needed to escape the mechanisms responsible for resistance.Additionally, two strategies for drug design were applied: multiple-loading andmultifunctional therapy approaches. Ferrocenyl compounds loaded with two molecules ofchloroquine and mefloquine were synthesized and characterized. Similarly, ferrocenylderivatives of chloroquine and mefloquine were further derivatized with a monossacharidemolecule. The double-loaded compounds are the first few examples of their kind. Themultifunctional conjugates improved the antimalarial action of the ferrocenyl quinolinederivatives.

View record

Acyclic chelates for imaging with radiometals (2011)

This thesis investigates acyclic chelates containing pyridine, carboxylate and amino groups and their fast and efficient and stable coordination of the (radio-)metals ⁹⁹mTc, Re, Cu, ⁶⁴Cu, Ga, ⁶⁷/⁶⁸Ga. The radiometals mentioned are all of significant interest for SPECT (single photon emission computed tomography) and PET (positron emission tomography) imaging, two of the most important non-invasive diagnostic tools in the clinic. The design, synthesis, radiolabelling, evaluation of stability, and in vivo investigation are presented for three variably charged, novel, short C₈ chain derivatized chelates for the [M(CO)₃]+ core (M = ⁹⁹mTc or Re). Distinct localization of these small amphiphilic molecules in vivo was studied via biodistribution and imaging and was found to be dependent on the charge of the polar moiety. In an attempt to identify a universal chelate applicable to the [M(CO)₃]+ core and ⁶⁴Cu, the synthesis of the dipin bifunctional chelate system, capable of fast coordination of Cu, its radionuclide ⁶⁴Cu, as well as the [M(CO)₃]+ core (M = ⁹⁹mTc, Re) is described. The versatility of the dipin ligand system is based on its ability to adopt a variety of binding modes, tridentate when protected, tetradentate when deprotected. Based on this small, tetradentate scaffold, a series of acyclic chelates with varying bite angle and denticity were synthesized and screened for their ability to coordinate radioisotopes of Ga and Cu under mild conditions within a short period of time. It was found that the linear N₄O₂ chelate H₂dedpa coordinates ⁶⁷/⁶⁸Ga quantitatively to form [⁶⁷Ga(dedpa)]+ after 10 min at room temperature with exceptional kinetic inertness towards human apo-transferrin. The corresponding ⁶⁴Cu complex maintains inertness against serum proteins within 2 h, but shows 23 % transchelation to serum proteins after 24 h. Both potential small molecule perfusion agents, as well as peptide conjugated versions as applications of the H2dedpa scaffold are reported. Both types of derivatives maintained the labelling and radiolabelled complex(⁶⁷/⁶⁸Ga and ⁶⁴Cu) stability properties found with the non-derivatized versions, further indicating the H₂dedpa scaffold is a useful platform for the development of clinically applicable radiopharmaceuticals.

View record

Investigation of Cysteine and Methionine Oxidation Using X-Ray Absorption Spectroscopy (2010)

Cysteine (Cys) and methionine (Met) are sulfur containing amino acids with various oxidation forms. Oxidation of Cys yields cysteinyl radicals that have been postulated as intermediates in several biological contexts including enzymatic catalysis, long-range electron transfer, peptide post-translational modification and cellular redox signaling. The challenges of detecting sulfur-based radicals with electron paramagnetic resonance (EPR) have led to the development of Sulfur K-edge X-ray absorption spectroscopy (S K-edge XAS) as a spectroscopic tool. The reactivity of sulfur-based radicals was studied in a Pseudomonas aeruginosa azurin protein system to probe the electronic structure of isolated cysteinyl radicals, which are characterized by S 3p ← 1s pre-edge transition. S K-edge XAS has shown to be a sensitive method in detecting these cysteinyl radicals in hydrophobic and hydrophilic protein environments. The pre-edge feature of the cysteinyl radicals in hydrophobic environments was lower in energy than their hydrophilic counterparts due to hydrogen bonding interactions. Additionally, S K-edge XAS was employed to study the redox photochemistry of Met and its oxidized forms methionine sulfoxide (MetSO) and methionine sulfone (MetSO₂). Met is easily photooxidized to MetSO and MetSO₂ in the presence of O₂. In the absence of O₂, photoirradiation leads to the one-electron-oxidized Met cation radical (MetS•⁺), suggesting an alternative mechanism for photooxidation of thioethers through direct oxidation. The photoirradiation of MetSO leads back to Met under both aerobic and anaerobic conditions while MetSO₂ is photochemically inert. These findings provide new insights into the formation of age-related cataracts. Finally, the metal-induced Met oxidation in amyloid-β (Aβ) peptide was investigated. Much of the research to date has focused on the redox chemistry of Cu²⁺ in Aβ peptide with inconsistent findings with regards to the role of Met₃₅ and the oxidation state of the Met₃₅. Findings reported here indicate that in the presence of Cu²⁺ alone, Met₃₅ was oxidized to MetSO, but surprisingly Fe³⁺ failed to oxidize the Met. These differences in the oxidation behaviour lead to the investigation of the metal binding site in Aβ. Fe³⁺ found to be in a six-coordinate environment with oxygen-rich ligands while Cu²⁺ is in a five-coordinate environment with histidine-rich ligands.

View record

Multifunctional pro-ligands as potential Alzheimer’s disease therapeutics (2009)

Alzheimer’s disease is the most common form of dementia, affecting more than 24 million individuals worldwide. Although the exact causes of disease development and progression are unknown, the amyloid hypothesis links the observed pathologies of elevated metal ion levels (Cu²⁺, Fe³⁺, Zn²⁺), deposition of amyloid peptide in senile plaques, oxidative stress and neurodegeneration in a cohesive manner. As part of a possible intervention for this process, a series of multifunctional pyridinone pro-ligands were designed and synthesised. 3-Hydroxy-4-pyridinones display a high affinity for metal ions - particularly Fe³⁺ and Cu²⁺ - and are readily functionalised by variation of the N-substituent on the heterocyclic ring. The alpha-hydroxyketone functionality serves not only to bind metal ions, but as an antioxidant via phenolic hydrogen donation; in addition, these activities may be masked by glycosylation at the 3-hydroxy position.Seven pyridinone pro-ligands were synthesised, each containing a pyridinone moiety and a second aromatic ring. Five of these pro-ligands incorporate structural features of amyloid imaging agents: 2-methyl-3-hydroxy-1-(4-dimethylaminophenyl)-4(1H)-pyridinone (Hdapp), 2-methyl-3-hydroxy-1-(4-methylaminophenyl)-4(1H)-pyridinone (Hsapp), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hzapp), 1-(6-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt6p) and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (Hbt2p). The final two compounds, 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (Hppp) and 1-benzyl-3-hydroxy-2-methyl-4(1H)-pyridinone (Hnbp), were synthesised and compared to probe the impact of linker length modification between the two aromatic rings. In addition to pro-ligand synthesis, their activities were assessed using a number of in vitro assays. Ability to interfere with metal ion-induced amyloid peptide aggregation in solution, antioxidant activity, cytotoxicity, coordination of Cu²⁺ and binding to amyloid fibrils were all assayed on this series. This was done as a preliminary screen to identify promising lead compounds for further development. The compounds displayed marked ability to resolubilise metal ion-aggregated amyloid-beta, excellent antioxidant activity comparable to that of alpha-tocopherol and acceptable cytotoxicity levels. Furthermore, the ligands coordinate Cu²⁺ in the bis, square planar, tetracoordinate fashion typical of 3-hydroxy-4-pyridinones, and their binding to amyloid-beta fibrils was found to be dependent on ring structure.This work incorporates the first examples of rationally-designed small-molecule Alzheimer’s therapeutics incorporating such multifunctionality, and it is expected that the combination will promote more effective Alzheimer’s intervention than current metal ion-binding therapeutics such as clioquinol and other 8-hydroxyquinoline derivatives in development.

View record

Radiolabelled carbohydrate conjugates : studies of Alzheimer's disease therapeutics and tumor imaging (2009)

This thesis is split into two distinct parts, with the common theme being the radiolabeling ofcarbohydrate-conjugates. Chapter 2discusses radioiodinating 3-hydroxy-4-pyridinones, ofinterest in treating Alzheimer’s disease. Chapters 3 - 5describe glucosamine conjugates of⁹⁹mTc investigated as potential carbohydrate-based SPECT imaging agents.Alzheimer’s disease (AD) sufferers develop characteristic beta-amyloid plaques in their brains,made up of beta-amyloid protein with high concentrations of zinc and copper. The redox activecopper ion can form reactive oxygen species (ROS) which damage surrounding tissue and leadto cell death. 3-Hydroxy-4-pyridinones are of interest in the treatment of AD because they areantioxidants and metal chelators, targeting both the plaques and ROS. Functionalisation of thesepyridinones with a glucose moiety masks the chelating portion of the molecule, and mayfacilitate blood brain barrier (BBB) crossing via the GLUT glucose transporters. To determinethis BBB permeability, two compounds were labelled with ¹²⁵1 and then assessed using aratbrain perfusion procedure. They were observed to cross the BBB, a crucial finding in thedecision to pursue this line of research for AD therapy.A⁹⁹mTc..based SPECT tumor imaging agent would increase worldwide access to the importantdiagnostic tools of nuclear medicine. Chapters 3 - 5discuss the synthesis, characterization andassay results of several monoanionic glucosamine-appended tridentate ligands and theircomplexes with the ⁹⁹mTc and Re tricarbonyl cores. The length of the linker between theglucosamine and the metal binding portion of the molecule range between two and elevencarbons. The binding moiety was also varied to give a library of molecules with differentbinding groups and linker lengths; useful for structure-activity relationship determination in arange of assays. The interaction of the compounds with hexokinase was assessed, and none ofthe compounds were found to be substrates for hexokinase. Transport of the compounds intocells by the GLUT transporters was also assayed, and found to be insignificant for allcompounds tested. Valuable information on the tolerances of these proteins was discovered andChapter 6includes ideas for improvements in future compounds.

View record

Master's Student Supervision

Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.

Hydroxamate-based non-macrocyclic chelators for zirconium-89 and other isotopes of hard metal ions (2019)

The development of radiopharmaceuticals for imaging and therapy has become a major focus in the field of cancer treatment. Bifunctional chelators (BFCs) attach to bioconjugates that allow for targeted radiation. This thesis examines the hydroxamate-based (hydroxamic acid) ligands for hard radiometal ions, such as zirconium-89. The current gold standard for ⁸⁹Zr⁴⁺ complexation is the chelating siderophore, desferrioxamine, a hexadentate ligand that has been shown to have stability issues for complexation with ⁸⁹Zr⁴⁺. New hydroxamate ligands have shown that flexibility is an issue for having four arms bind to ⁸⁹Zr⁴⁺. The potentially octadentate, hydroxamate-based ligand, H₄octaha (1), was designed to overcome the flexibility issue. The synthesis of H₄octaha (1) encountered issues with the formation of a side reaction when synthesizing a protected arm and the selectivity of amines when alkylating the dien backbone. These issues led to the development of a new ligand, H₅decaha (2). H₅decaha (2) is a potentially decadentate, hydroxamate-based ligand that was designed to solve the issues with the synthesis of H₄octaha (1). The synthesis of the ligand was completed; however, the yield was too low for analysis by ¹H NMR and ¹³C NMR. Initial complexation test for H₅decaha (2) with Ga³⁺ suggest that the ligand was synthesized and H₅decaha (2) complexes with a Ga³⁺ ion and two Na⁺ ions. The ligand H₄noonha (3) is a potentially octadentate, hydroxamate-based ligand that uses 1,2-bis(aminoethoxylethane) as a backbone replacing dien. The ligand was synthesized and analyzed by ¹H NMR spectroscopy; however, due to a contaminant, additional analyses could not be completed. Additional synthesis attempts were made; however, not enough product was obtained to continue the analysis for characterization. The functionalized dien (4) was synthesized to make H₄octaha (1) and H₅decaha (2) into bifunctional chelators. Purification by reduced pressure and column chromatography were not successful. The backbone was precipitated out as an HCl salt, which suffers from insolubility issues making analysis difficult.

View record

Synthesis and Characterization of H5decapa and Related Ligands (2015)

Radiopharmaceuticals have provided a great breakthrough in tumor imaging and treatment, and the continued exploration in the field is required to make their use widespread. This vast potential lies in the variety of the radioisotopes, due to the different emission profiles and half-lives, and it is the chemist’s job to harness these isotopes into functional pharmaceuticals. Bifunctional chelators (BFC), that incorporate a radiometal into a ligand scaffold that is functionalized to target a specific biological site, provide a mode to access many of these isotopes: α, β-, or auger electron emitters for therapy, β+ emitters for positron emission tomography (PET) imaging, and γ emitting isotopes for single photon emission computed tomography (SPECT) imaging. The first requirement of a BFC is the thermodynamic stability and kinetically inert complex it forms with the isotope, especially in vivo. The Orvig group has discovered the promise of the ligands H₂dedpa for ⁶⁷/⁶⁸Ga and H₄octapa for ¹¹¹In, and has thus led to the idea of expanding this scaffold for larger radioisotopes. An improved synthetic scheme for H₅decapa, a decadentate ligand, allowed for thermodynamic testing and radiolabeling experiments to be performed with ⁸⁹/⁹⁰Y, ¹⁷⁷Lu and ⁸⁹Zr. H₅decapa showed promising serum stability over 5 days with ¹⁷⁷Lu, and was able to quantitatively bind ⁸⁹Zr after 30 minutes at room temperature. A bifunctional version of H₅decapa was synthesised, coupling para-nitroethylbenzene to the central nitrogen, for future conjugation to biomolecules. As well, preliminary investigation into creating a version of H₅decapa with hydroxamate groups catered to binding Zr⁴⁺ was undertaken.

View record



If this is your researcher profile you can log in to the Faculty & Staff portal to update your details and provide recruitment preferences.


Read tips on applying, reference letters, statement of interest, reaching out to prospective supervisors, interviews and more in our Application Guide!