Toxicity and biological activity of natural products

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The use of natural product-based remedies to maintain good health or treat disease has been known for centuries, and in recent years the use of natural health products has increased in Canada. Beneficial effects observed with natural health products are the result of the actions of the specific natural products present, unfortunately a great deal remains poorly understood regarding their safety and effectiveness. Our research program is aimed at developing a better understanding of how some natural health products work and has two major components. First, we are investigating the fundamental chemical properties of polyphenolic natural products and how they may help us to learn about their health benefits. One research focus is on a group of compounds called lignans. A lignan in flaxseed (SECO) is associated with improved heart health and cancer treatment, whereas a lignan found in the creosote bush (NDGA) has both beneficial effects and causes liver and kidney toxicity. We have determined that NDGA is metabolized to a toxic compound but can also form a new compound (cNDGA) which appears to have interesting biological properties. We are synthesizing novel lignan analogues that will allow us to determine what structural factors control the reactions of lignans and related natural products such as triphenyl ethanes (found in maple syrup) and how this may influence their stability and function as natural health products. A second focus of our program is the development of probe molecules based on the structure of natural products in order to study the mechanisms of how natural products interact with biological targets. Our current model will investigate the interaction with disordered proteins which aggregate under certain conditions. One method adds a short-lived radioisotope (18F) to a natural product which is then monitored via techniques including positron emission tomography to assess how these compounds interact with disordered proteins. A second method will introduce a group in the molecule called a photoaffinity label, which is activated by ultraviolet light, and results in the labeled natural product attaching to the protein. This provides information about the location on the disordered protein that the natural product interacts with and improve our understanding of how compounds may prevent or induce aggregation of the disordered proteins. The information created through this research will be critical to develop models to predict the stability of lignans, polyphenols and other natural products and to use this to develop diagnostic tools for understanding aggregation properties of disordered proteins.