Toxicity and biological activity of natural products

使用以天然产品为基础的疗法来保持身体健康或治疗疾病已经有几个世纪的历史了，近年来，加拿大对天然保健产品的使用有所增加。观察到的天然保健品的有益效果是存在的特定天然产品的作用的结果，不幸的是，关于它们的安全性和有效性，人们仍然知之甚少。我们的研究项目旨在更好地了解一些天然健康产品的工作原理，它有两个主要组成部分。首先，我们正在研究多酚类天然产物的基本化学性质，以及它们如何帮助我们了解它们对健康的益处。一项研究的重点是一组被称为木脂素的化合物。亚麻籽中的木脂素（SECO）与改善心脏健康和癌症治疗有关，而在杂酚灌木（NDGA）中发现的木脂素既有有益作用，也会导致肝脏和肾脏毒性。我们已经确定NDGA被代谢成一种有毒化合物，但也可以形成一种新的化合物（cNDGA），这种化合物似乎具有有趣的生物学特性。我们正在合成新的木脂素类似物，这将使我们能够确定哪些结构因素控制木脂素和相关天然产物（如三苯基乙烷（在枫糖浆中发现））的反应，以及这可能如何影响它们作为天然保健产品的稳定性和功能。我们计划的第二个重点是基于天然产物结构的探针分子的发展，以研究天然产物如何与生物靶点相互作用的机制。我们目前的模型将研究在特定条件下聚集的无序蛋白质的相互作用。一种方法是在天然产物中加入一种短寿命的放射性同位素（18F），然后通过正电子发射断层扫描等技术对其进行监测，以评估这些化合物如何与无序蛋白质相互作用。第二种方法是在分子中引入一种被称为光亲和标签的基团，它被紫外线激活，并导致标记的天然产物附着在蛋白质上。这提供了有关天然产物与无序蛋白相互作用的位置的信息，并提高了我们对化合物如何预防或诱导无序蛋白聚集的理解。通过这项研究创造的信息对于开发预测木脂素、多酚和其他天然产物稳定性的模型至关重要，并将其用于开发诊断工具，以了解无序蛋白质的聚集特性。

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.