Organic Synthesis of Biologically Interesting Compounds and Organosulfur/Selenium Chemistry

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Our program is in the area of synthetic organic chemistry, generally directed toward biologically interesting molecules, with special emphasis on organosulfur/selenium compounds. More specifically, we are studying selenium redox chemistry, total synthesis of alkaloids and novel antiprotozoan agents. We discovered several highly effective compounds that mimic the antioxidant enzyme glutathione peroxidase (GPx) and are now working on improving their catalytic activity and elucidating their mechanisms. Such compounds complement GPx in catalytically reducing harmful peroxides and decreasing the high levels of oxidative stress that occur during reperfusion treatment of heart attacks/strokes, and in many other diseases and degenerative conditions. The “flip side” of redox chemistry of GPx mimetics is the catalysis of oxidations of organic substrates with hydrogen peroxide, a cheap, environmentally benign oxidant. Some of our novel GPx mimetics effectively catalyze several synthetically useful oxidations, such as epoxidations. Our objective is to improve our mechanistic understanding of these reactions, to expand their scope and to develop enantioselective variations. We engage in the total synthesis of alkaloids, partly because of their bioactivities but mainly for the wealth of new chemistry that is typically discovered during such endeavours. Our principal target is currently cylindricine C, a scarce marine alkaloid with an unusual tricyclic structure, and its congeners. A new approach to the design and synthesis of antiprotozoan drugs is based on the purine salvage pathway found in protozoa, but not in mammals. We have prepared a series of nucleoside-based antimetabolites that were tested against four pathogens by the Swiss Tropical Disease & Public Health Institute. We currently have lead compounds against malaria and leishmaniasis with nanomolar IC50 activities and remarkable therapeutic selectivities of 1010 and 2720, respectively, with respect to their relative toxicities to the pathogen and a mammalian cell line. The synthesis of new analogues, based on structure-activity relationships of those prepared to date, is continuing. These products will be tested for antiprotozoan activity by our collaborators in Switzerland. Potential benefits to Canada: 1) Heart attacks and strokes are a leading cause of death and an economic liability. Reducing neurological and cardiovascular damage from such events has obvious benefits. 2) Novel catalysts for oxidation processes are of importance in both the laboratory and industry in the preparation of e.g. pharmaceuticals and industrial chemicals. 3) New methods for the synthesis of alkaloids are often applicable to other nitrogen heterocycles, including core structures of many current drugs. 4) Internationally, protozoan diseases affect millions and cause hundreds of thousands of fatalities each year. Existing drugs are encountering resistant pathogens and there is an urgent need for new therapies.