Development of Enabling Methods for Natural Product and Medicinal Chemistry

在过去的25年里，FDA批准的50%以上的药物是天然产品，或者是受天然产品的启发而在治疗领域领先的。虽然天然产品对人类健康的重要性是显而易见的，但通常从天然来源获得的材料数量有限，或与收获生产生物体有关的环境问题阻碍了它们发展成药物。此外，许多天然化合物的结构复杂性会使它们的开发进一步复杂化。因此，天然产物发现的充分实现往往依赖于合成有机化学的同时突破，这是在实验室中制备有用数量的这些化合物所必需的，并探索它们的结构和生物活性之间的关系。考虑到这一点，本研究计划的长期目标是通过关注以下发现主题来解决天然产物和药物化学中的基本挑战：i)可以应用于快速合成天然产物和药物中常见的“特权”分子结构的新方法；Ii)定向合成具有潜在有用生物活性的稀缺天然产物；（三）发展可用于核医学目的的新的氟化反应。特别是，我们计划开发两种具有治疗癌症潜力的天然产物——伊柳红蛋白和双糖苷A的合成，以及两个独立的亚糖和碳水化合物模拟物家族，这可能使未来在治疗细菌感染和阿尔茨海默病方面取得突破。此外，我们将研究用氟取代各种有机分子中的氢原子的新反应。最终，这些氟化反应将导致发现用于肿瘤正电子发射断层扫描（PET）成像的改进的放射性示踪剂。这项研究计划应该通过为从事天然产物和药物发现以及核医学的研究人员提供有利的技术和方便的方法来影响更广泛的社区实践。通过药物的下游开发和改进的放射性示踪剂，用于早期发现癌症，这项研究的预期结果将对加拿大人的健康产生重大和积极的影响。

Over 50% of drugs approved by the FDA in the past 25 years are natural products or were inspired by a natural product lead in the therapeutic area. While the importance of natural products to human health is clear, oftentimes the limited amounts of material available from the natural source, or environmental concerns associated with harvesting the producing organism prevent their development into drugs. Additionally, the structural complexity of many naturally occurring compounds can further complicate their development. Thus, the full realization of natural product discoveries often relies on simultaneous breakthroughs in synthetic organic chemistry necessary to prepare useful quantities of these compounds in the laboratory, and explore the relationship between their structure and biological activity. Bearing this in mind, the long term goal of this Research Program is to address fundamental challenges in natural product and medicinal chemistry by focusing on the following discovery themes: i) new methods that can be applied to the rapid synthesis of 'privileged' molecular structures that are common to both natural products and pharmaceuticals; ii) directed synthesis of scarce natural products that have potentially useful biological activity; and iii) development of new fluorination reactions that can be exploited for the purpose of nuclear medicine. In particular, we plan to develop syntheses of eleutherobin and biselide A, two natural products that hold potential for the treatment of cancer, and two separate families of iminosugars and carbohydrate mimics that may enable future breakthroughs in the treatment of bacterial infections and Alzheimer's disease. In addition, we will investigate new reactions that replace hydrogen atoms in various organic molecules with fluorine. Ultimately, these fluorination reactions should lead to the discovery of improved radiotracers for positron emission tomography (PET) imaging of tumors. This Research Program should impact the practices of the wider community by providing enabling technologies and convenient methods for researchers engaged in natural products and drug discovery, and nuclear medicine. Through the downstream development of drugs and improved radiotracers for early detection of cancer, the anticipated outcomes of this research will have a significant and positive impact on the health of Canadians.