Grant: Discovery Grants Program - Individual

This proposal supports multidisciplinary training in organic chemistry; Our long-term vision is to devise new synthetic methods and synthesize new molecules to answer important questions and solve problems in chemistry and biology. Research is fundamental and addresses significant challenges in methodology, synthesis, molecular recognition, and catalysis with applications in fine-chemical synthesis, imaging, medicinal chemistry and the design of the next generation of "smart drugs" and sensors made of DNA. Our preliminary data and ongoing work and recent publications augur for success in these goals. Specifically, we will advance knowledge through the pursuit of five long-term goals not funded by other grants. 1.Synthesize bioactive natural products and peptides based on novel modified indoles: We will synthesize challenging compounds featuring new work on modified indoles (a natural heterocycle). These bring new synthetic know-how and new probes for key biological targets. 2.Develop late-stage fluorescent isoindole stapled peptide macrocycles: Based on our discovery of fluorescent isoindole peptide stapling, we will develop a powerful chemical platform to discover high-affinity peptides with emergent fluorescence to provide tools for cell-based screens and confocal studies. 3.Synthesize new RBF3s as isosteres for applications in biology: Organotrifluoroborates (RBF3s) are anions that mimic carboxylates in biology. Excitingly, RBF3s enable facile PET imaging, an application that we invented. We propose new methods for synthesizing new RBF3s that will be studied in biochemical assays. 4.Use Organofluoroborates for C-F Bond Formation: Fluorinated compounds are highly prized in agrichemicals, pharmaceuticals and materials but are difficult to prepare. Our interest in RBF3s led us to discover a new application where RBF3s can be used as cheap reagents to fluorinate carbon. Novel methods are proposed to exploit this. 5.Expand chemical functionality in DNAzymes & aptamers for sensing, imaging, and therapeutic leads: DNA is an exciting technological platform for selecting catalysts and ligands capable serving as "smart drugs" and sensors. Here we will merge chemical synthesis and molecular biology to evolve novel hybrid DNA catalysts that contain protein-like functionalities for enhanced specificity and activity. These projects represent new and risky ideas that have the high potential for breakthroughs that can be spun out for additional funding by agencies and industries that will fund highly applied projects based on more mature results. The multidisciplinary nature of this proposed research and the training it provides is unparalleled in Canada in terms of the breadth and depth. With a track record of publishing and training in these five above subjects, along with a record of leveraging and commercializing previous NSERC-funded work, we are uniquely qualified to execute on these goals.