Reaction Mechanisms and Methodology for the Design and Synthesis of Bioactive Agents.

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The main objective of our research program is to develop novel methodologies and strategies to access challenging molecular scaffolds. Our research program will benefit Canadians through the advancement of our collective knowledge in chemistry and should also bring positive socio-economical impacts and health benefits. Some of our novel nucleoside analogues demonstrate remarkable activity against pancreatic cancer cell lines that do not respond to the clinical gold standard of treatment (Gemcitabine). Another family of molecules of this class protects the heart against cardiotoxic agents, such as anticancer drugs, and is remarkably active in heart failure models. These advancements were born out of our long-standing interest in free-radical based chemistry combined with our commitment to develop alternative methods to prepare nucleoside analogues. The highly reactive nature of radical intermediates was harnessed to produce stereogenic all-carbon quaternary centers that can be introduced at C3' or C2' of nucleoside scaffolds. Our key strategy for the synthesis of nucleoside analogues involves diastereoselective formation of acyclic thioaminals by introducing a nucleobase on dithioacetals, followed by kinetically controlled cyclizations. We plan to further improve the synthesis of our lead molecules and prepare photoaffinity probes to elucidate their mechanism of action in collaboration with research groups with expertise in cancer and cardioprotection. The free-radical approaches will also be applied to synthesize biologically relevant terpenes and analogues thereof, such as dictyoceratins A and C, a potential new avenue to antiproliferative agents. Finally, we are actively working on the discovery of E- and P- selectin antagonists that are key mediators in the immune system's inflammatory response. The objective of our synthetic design is to restrict the relevant pharmacophores of the endogenous polysaccharide, sialyl LewisX (sLeX), to mimic analogues that are locked in the bioactive conformation. This project stimulated us to elaborate efficient strategies to prepare bicyclic-like analogues of natural sugars that could find various biological applications.