Christopher E 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.

Professor

Research Classification

Chemical Synthesis and Catalysis
Imaging
Inorganic and Organometallic Compounds
Nuclear medicine
Chemical Processes
Chemotherapy

Research Interests

medicinal inorganic chemistry
coordination chemistry
radiopharmaceutical chemistry
bioinorganic chemistry
ligand design and synthesis

Relevant Degree Programs

 

Graduate Student Supervision

Doctoral Student Supervision (Jan 2008 - May 2019)
Metallodrugs for therapy and imaging : investigation of their mechanism of action (2018)

The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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