Development of Enabling Methods for Natural Product and Medicinal Chemistry

在过去的25年里，FDA批准的药物中有超过50%是天然产品或受到治疗领域中天然产品铅的启发。虽然天然产品对人类健康的重要性是显而易见的，但从自然来源获得的材料数量有限，或与收获生产有机体有关的环境问题往往阻碍了它们发展成为药物。此外，许多天然化合物的结构复杂性可能会使它们的发展进一步复杂化。因此，完全实现天然产物的发现往往依赖于在实验室制备有用数量的这些化合物并探索它们的结构和生物活性之间的关系所必需的合成有机化学的同时突破。考虑到这一点，该研究计划的长期目标是通过专注于以下发现主题来应对天然产品和药物化学中的根本挑战：i)可用于快速合成天然产品和药物共同的“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有天然产品；以及iii)开发可用于核医学目的的新的氟化反应。具体地说，我们计划开发两种具有治疗癌症潜力的天然产品Eleutherobin和Biselide A的合成，以及两个独立的亚氨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，我们还将研究用氟取代各种有机分子中的氢原子的新反应。最终，这些氟化反应应该会导致发现用于正电子发射断层扫描(PET)肿瘤成像的改进的放射性示踪剂。这一研究计划应该通过为从事天然产品、药物发现和核医学的研究人员提供使能技术和方便的方法来影响更广泛社区的实践。通过下游药物的开发和用于癌症早期检测的改进的放射性示踪剂，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.