Chris Orvig

Professor
( Joint with Pharmaceutical Sciences )

Office: Chemistry D316
Office Phone: (604) 822-4449
Lab(s): Chemistry D419/D422
Lab Phone(s): (604) 822-8632

FAX: (604) 822-2847
Email: orvig@chem.ubc.ca

Curriculum Vitae: B.Sc., McGill University (1976); Ph.D., MIT - NSERC Postgraduate Scholar (A. Davison, 1981); NSERC Postdoctoral Fellow, University of California, Berkeley (K. N. Raymond, 1981-83); Postdoc, McMaster University (C. J. L. Lock, 1983-1984); Fellow, Chemical Institute of Canada; Director, Medicinal Inorganic Chemistry Group. UBC Faculty of Science Killam Teaching Award 1998. Alexander von Humboldt Foundation Research Award 1999-2000. UBC Killam Research Prize 2005-6. University of Sydney Foundation for Inorganic Chemistry lecturer 2006. Japan Society for the Promotion of Science Invitation Fellow 2007. Rio Tinto Alcan Award, Canadian Society for Chemistry, 2009. Royal Society of Chemistry Bioinorganic Chemistry Award, 2009.

Medicinal Inorganic Chemistry: Medicinal inorganic chemistry. Synthesis, physical studies, solution chemistry and structural analysis of coordination compounds of biological or medical importance; coordination chemistry of the f-elements; bioinorganic chemistry of main group elements; in vivo biodistributions and toxicology; in vitro cell studies; radiopharmaceutical chemistry; vanadium complexes as therapeutic agents for diabetes.

  View Publications     review in Science     Centre for Blood Research     C-HORSE  

Research/Teaching Interests

TEACHING PHILOSOPHY

My basic teaching philosophy is to be enthusiastic about my subject, honest about potential confusions, and unambiguous in my explanations. I involve students in every lecture through a variety of mechanisms (call-and-response, intimate tutorials in which the students tell each other the answers using the chalkboard and I act as a facilitator, spot-the-trend checks, student papers/seminars, etc.). I try to make students feel that the lecture could not take place without them. I extensively use clear handouts so that the principles, not the details, are emphasized as being of importance. I de-emphasize memory work, and I stress the importance of integration of knowledge in the problem sets and exams (I tell the students this). Regurgitation is not part of my teaching philosophy.

RESEARCH PROGRAMME

Research projects in our labs study the roles of metal ions in the etiology, diagnosis, and therapy of disease. These projects encompass a variety of metal ions as well as numerous ligand systems and a wide panoply of techniques and collaborations. Synthesis of organic ligands and inorganic complexes as well as physical (potentiometric and spectrophotometric titrations, various spectroscopies, electrochemistry etc.) and biological studies (in cells, at UBC Bioservices and/or in collaboration) are undertaken in the research programme.

Glycosylated Pro-drugs for Metal Passivation in Neurodegenerative Diseases

The amyloid hypothesis seeks to explain the aetiology of Alzheimer’s disease (AD) by linking irregularities present in the affected brain, insoluble aggregates of beta-amyloid (A-beta) protein and elevated levels of redox active metal ions, with the observed symptoms of oxidative stress and brain tissue damage. Beta-amyloid is a ubiquitous, normal brain protein that, in the case of AD, becomes pathogenic through an unknown mechanism. While currently available therapeutic strategies such as the administration of cholinesterase inhibitors focus on relief of symptoms of AD (in this example, reduced neuronal activity), we have developed with Prof. H. J. Schugar of Rutgers University and our collaborators, a strategy which seeks to target two brain pathologies described in the amyloid hypothesis: elevated levels of metal ions and oxidative stress. Our strategy seeks to obtain synergistic benefits from multifunctional drugs that bind and passivate redox active metal ions (i.e., Cu(II), Zn(II), Fe(III)) while also being potent inhibitors of the free radical oxidative processes that can lead to neurological tissue destruction. In addition, glucose substituents are incorporated into the compounds to promote prodrug uptake by the brain. Every compound is designed to include: 1) carbohydrate substituent(s) for improved central nervous system (CNS) access; 2) antioxidant functionality for reduction of oxidative stress conditions; and 3) metal chelation capabilities to sequester excess CNS metal ions. Prototype compounds have been synthesized, characterized, studied and patented in order to compare multiple variations of the two classes of designed multi-functional compounds through cell cytotoxicity and pharmacokinetic profiling, to identify lead compounds that can be used in further in vitro and in vivo studies. This novel strategy has potential synergistic benefits for both prevention and treatment of neurological disorders, including Alzheimer’s and Parkinson’s diseases, and goes well beyond currently proposed therapies that either target reactive oxygen species (ROS), or non-specifically bind excess metal ions in the tissues of neurodegenerative disease patients.

Ferrocenyl-carbohydrate Conjugates in Malaria

Malaria is a widespread parasitic disease that affects a large population. Four species of the human infecting parasite are known, plasmodium falciparum being the most lethal of these. It is estimated that 2 billion people have been exposed to the parasite; yearly, 300-500 million new cases are reported and between 1 and 2.7 million people die from the infection. Historically, malaria is found in tropical areas, including the poorest countries. Although the majority of cases originate in Africa, Southeast Asia, India, and parts of South America, the disease is now threatening to spread into more temperate zones of the world and global warming would certainly facilitate this reach. Currently, no commercially available vaccine for malaria exists, and drug resistance is becoming rampant. The need for different categories of anti-malarials, active against the resistant strains, has risen. Unfortunately, scant funding for a poor person’s disease has led to insufficient research for novel drugs and treatments for malaria. Some alternative drugs are being investigated, but are either costly or have adverse side effects, such as toxicity. An attractive area of research for new malarial treatment is directed metal conjugates, particularly those of known anti-malarial drugs. Ferrocene has several properties which have facilitated its investigation for potential biological applications. Typically, organometallic compounds are sensitive to moisture and air, but ferrocene belongs to a unique group thereof whose members are stable under both aqueous and aerobic conditions. The small size, relative lipophilicity, easy chemical modification, and accessible one electron oxidation potential of ferrocene make it an attractive reporter moiety and an intriguing pharmaceutical vector. Ferrocenoyl carbohydrate conjugates have potential as metalloantimalarials. Combining the ferrocene moiety with a glucose derivative is a novel approach for developing targeted therapy. The ferrocene moiety has proven to be a successful addition to known malaria therapeutics, increasing efficacy towards chloroquine resistant strains of the parasite. As well, glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle and glucose consumption has been a target in anti-malarial research. The hypothesis of this work is that ferrocene-carbohydrate conjugates have the potential to retain activity in chloroquine resistant parasite strains, and to have increased efficacy by targeting infected cells. This work studies the cytotoxicity and anti-plasmodial activity of several ferrocene carbohydrate conjugates, and includes the synthesis and characterization of numerous new ferrocene carbohydrate conjugates. With Dr. M. J. Adam of TRIUMF, we have published some preliminary studies showing that ferrocenyl carbohydrate conjugates exhibit some selective anti-malarial activity - glucose uptake and metabolism in infected erythrocytes is elevated at all stages of the parasite’s life cycle. The main goal of the project is to synthesize new ferrocenyl-carbohydrate conjugates that are inexpensive to produce, have activity in chloroquine-resistant parasites strains and that will have increased efficacy by targeting infected cells.

Lanthanide Compounds for Bone Resorption Disorders

Bone density disorders, including osteoporosis, affect 1 in 4 women and 1 in 8 men over age 50 in North America; as the population ages, these diseases are incurring substantial annual health care costs escalating into billions of dollars. Osteoporosis is characterized by low bone mineral density that leads to enhanced bone fragility and a consequent risk of low-impact bone fractures. The low bone mineral density is a result of an imbalance between bone resorption and bone formation. Normally, building and absorption of bone is a tightly regulated cycle wherein the bone matrix is manufactured by osteoblast cells and removed by osteoclast cells. Either increased activity of osteoclasts or decreased bone formation by osteoblasts leads to microarchitectural deterioration of bone tissue. Many contributing factors are known to influence the pathogenesis of the disease with the most prominent being inadequate calcium uptake. Few therapeutic agents exist currently, either for prevention or for amelioration of these serious diseases, and patient compliance with the existing treatments is low due to adverse gastrointestinal side effects and/or high costs. A new class of osteoporosis drugs, including oral strontium ranelate, stimulate osteoblast proliferation and inhibit osteoclast activity; however, uncertainty regarding the potential toxicity of chronic strontium accumulation in bone may limit the utility of this product. Lanthanides Ln(III) are known for their therapeutic and diagnostic applications as agents for magnetic resonance imaging, cancer and radiotherapy. Low doses of Ln have been shown to act similarly to strontium ranelate. In vivo, Ln(III), a functional mimic of Ca(II), has been found to exchange with Ca(II) in bone to modify the bone remodeling cycle by stimulating osteoblast proliferation and impeding bone resorption by inhibiting osteoclast differentiation. Based on this evidence, lanthanum carbonate (La2(CO3)3) has been proposed as a potential preventative measure for post-menopausal osteoporosis; however, gastrointestinal upset is a known negative side effect of this treatment. La2(CO3)3 is currently being used to treat hyperphosphatemia under the trade name of Fosrenol™. Unfortunately, due to its extremely low bioavailability (<0.0007%), high doses of elemental La(III) are administered for this application, leading to adverse gastrointestinal (GI) tract side effects. Adjustments to the ligand structure around the Ln(III) ions has the potential to increase the oral bioavailability of Ln(III) for the treatment of bone density disorders while decreasing unwanted side effects. In collaboration with Prof. K. Wasan of UBC’s Faculty of Pharmaceutical Sciences, we are investigating neutral Ln(III) tris(bidentate ligand) complexes using as bone agents. La(III), Gd(III), and Yb(III) ions were investigated, with selection of specific lanthanides based on their known medicinal applications and for size comparison and the potential of these compounds as therapeutic agents for the treatment of bone resorption disorders is being assessed in cytotoxicity studies, comparative bifunctional transport in human colon carcinoma cells with intestinal cell like properties (Caco-2 cells) and hydroxyapatite binding.

Coordination Chemistry of Metallic Isotopes in Nuclear Medicine

Our group works together with Dr. M. J. Adam at TRIUMF and the isotope supplier MDS Nordion to add value to their growing line of Nuclear Medicine radiometals. Positron Emission Tomography (PET) and Single Photon Emission Tomography (SPECT) are two imaging modalities that our aging population will depend upon for the early detection of disease, particularly in the area of oncology. PET has become the "gold standard" in the early detection of cancer which currently relies on the use of 18-fluoro-deoxy-glucose (18-FDG). New promising radiopharmaceuticals, more specific for disease processes, are being developed for both PET and SPECT. In order to achieve this goal new radiolabelling methods and chemistry are being discovered. Much of this advancement is made possible by the synthetic production of biomolecules (e.g. peptides, lipids, oligosaccharides, oligonucleotides and antibodies) with specific and high affinity for cancer biomarkers. The development of these ligands into viable imaging agents is being realized through the discovery of new robust, reproducible, high-yielding and rapid methods for introducing the radioisotope of choice into these biomolecules to give chemically stable entities, with a particular focus on conjugating Ga-68 or In-111 into biological molecules such as peptides, proteins, oligonucleotides, carbohydrates and fatty acids and to evaluate their biological properties as potential imaging or therapy agents.

Vanadium Compounds as Insulin-enhancing Pharmaceuticals

Vanadium has been known to have insulin-mimetic properties in vitro for decades; it was our collaborator Prof. John McNeill of UBC’s Faculty of Pharmaceutical Sciences, who showed in a diabetic rat model in 1985 that these properties could be used as a treatment in vivo. Naturally, to progress the field required designed pertinent compounds of vanadium, particularly for structure-activity relationships and for increased oral absorption, the key property necessary for agents with clinical potential in diabetes treatment. A number of vanadium compounds have been reported to have insulin-enhancing properties, most notably when administered orally (a route via which insulin is not active). Still, gastrointestinal absorption of vanadium is usually poor and depends on the chemical nature, solubility, and speciation of the specific metal ion complex. Little is known about the coordination properties of orally administered vanadium compounds in vivo, about the factors required to deliver vanadium to its ultimate site of action, or indeed the site of action. We have designed, synthesized and studied in detail vanadium compounds of the widely-used food additives maltol and ethylmaltol, bis(maltolato)oxovanadium(IV) (BMOV) and bis(ethylmaltolato)oxovanadium(IV) (BEOV), as well as with many other ligands. After preliminary studies of oral efficacy in diabetic rats, the use of this compound for a variety of indications was patented by UBC and the initial results were published in 1992 to significant notice. Subsequently, the research has been licensed and many collaborative studies of the coordination chemistry and biological efficacy are undertaken in the labs of Orvig and McNeill. Because of its oral efficacy and lack of toxicity, BMOV has become the benchmark for oral vanadium-containing insulin-enhancing compounds. BEOV is in clinical development for diabetic mellitus.