Development of new methods for the synthesis of biologically active natural products

开发合成具有生物活性的天然产物的新方法

• 批准号: 326980-2009
• 负责人: Britton, Robert
• 金额: $ 3.64万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2011
• 资助国家: 加拿大
• 起止时间: 2011-01-01 至 2012-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=481528
• 关键词: Development; new; methods; synthesis; biologically

It is difficult to overstate the importance of natural products to human health. The near doubling of the life expectancy for the average Canadian in the 20th century is largely attributed to medical advances based on natural products and over 50% of drugs approved by the FDA in the past 25 years are, or their origins can be traced to, natural products. Recent advances in biochemistry and molecular biology, that includes the development of high-throughput assays for rapidly identifying biologically active compounds, has enabled the discovery of many new natural products with a fascinating range of biological activities and structural diversity. However, due to often-limited amounts of material available from the natural source or environmental concerns associated with harvesting the producing organism, the full realization of these discoveries relies on simultaneous breakthroughs in synthetic chemistry, or total synthesis, necessary to assemble the biologically active compound in the laboratory. Thus, through total synthesis organic chemists provide a renewable source of the natural product, and generate sufficient quantities for unambiguous structural assignment and thorough biological testing. Bearing this in mind, the major focus of our research program is the total synthesis of natural products that represent potential lead candidates for the treatment of human diseases, and insect sex pheromones that provide earth-friendly alternatives to insecticides. These studies rely heavily on the development of innovative reactions that will allow us to construct complex natural products in a straightforward manner from simple chemical building blocks. In particular, we plan to develop reactions that will provide rapid access to haterumalide, a potential anticancer agent; hyacinthacine A5, a potential antidiabetic agent; and chimonanthine, an analgesic natural product. Our flexible syntheses of these molecules will also allow us to generate new substances, similar in structure to these natural products but with potentially improved pharmaceutical properties. The successful implementation of this program will enable discoveries fundamental to our basic understanding of organic chemistry and the development of pharmaceuticals.

天然产品对人类健康的重要性再怎么强调也不为过。20世纪，加拿大人的平均寿命几乎翻了一番，这在很大程度上要归功于基于天然产物的医学进步。在过去的25年里，美国食品和药物管理局批准的50%以上的药物都是天然产物，或者它们的来源可以追溯到天然产物。生物化学和分子生物学的最新进展，包括用于快速识别生物活性化合物的高通量分析的发展，使许多具有迷人生物活性和结构多样性的新天然产物得以发现。然而，由于从自然来源获得的材料数量通常有限，或者与收获生产生物体有关的环境问题，这些发现的充分实现依赖于合成化学或全合成的同时突破，这是在实验室中组装生物活性化合物所必需的。因此，通过全合成，有机化学家提供了天然产物的可再生来源，并为明确的结构分配和彻底的生物测试产生了足够的数量。考虑到这一点，我们研究项目的主要重点是天然产物的全合成，这些天然产物代表了治疗人类疾病的潜在主要候选物，而昆虫性信息素则提供了对地球无害的杀虫剂替代品。这些研究在很大程度上依赖于创新反应的发展，这些反应将使我们能够从简单的化学构建块中以直接的方式构建复杂的天然产物。特别是，我们计划开发能够快速获得haterumalide（一种潜在的抗癌剂）的反应；风信子A5，一种潜在的降糖药；还有chimonanthine，一种镇痛的天然产物。我们对这些分子的灵活合成也将使我们能够产生新的物质，在结构上与这些天然产物相似，但具有潜在的改进的药物性能。这一计划的成功实施将使我们对有机化学的基本理解和药物的发展产生根本性的发现。