The Chemistry and Biology of Resveratrol-based Oligomers

描述(申请人提供)：如果科学家要成功地解决社会面临的最大生物医学挑战，我们识别和创造具有独特性质的功能小分子的能力必须显著提高。长期以来，天然产物为这类研究提供了很好的起点，因为它们的结构经过数千年的演变，实现了特定的生化功能，它们的合成提高了我们的技能。然而，许多类别的此类结构仍未被开发。其中最重要的是低聚天然产物，即在自然界中由简单的积木通过故意不受控制的反应途径创建的化合物家族，化学家们从未能够在实验室中调节这些反应途径。这一提议寻求提供改变这一范式所需的创新合成解决方案，并最终以受控的方式访问这些类别的分子，从而能够探索它们的全部生化潜力。我们最初的试验场在于白藜芦醇天然产物家族，这是一类丰富的化合物，其性质在初始筛选中似乎非常适合丰富的发现计划，因为它们的结构独特性以及抗肿瘤、抗病毒、抗真菌、抗氧化和抗衰老行为(许多通过未知或独特的作用模式)。通过一种独特的合成策略的镜头来观察这些目标，我们展示了如何通过由最简单的试剂启动的一系列创造性的复杂性构建序列，从自然的起始材料中很好地移除单个常见的构建块，来组装整个类别(以及几个非自然结构)的多样化的碳素复杂性。然后，将与合作者一起对这些基本上未被探索的化合物进行彻底和深入的筛选，以阐明它们在关键生化事件中的作用，特别是与人类生物学有关的事件。与公共健康相关：该提案试图确定红酒中的酚类物质，如白藜芦醇和白藜芦醇衍生的分子，是否应为“法国悖论”负责。将对合成的化合物进行抗癌、抗病毒、抗衰老和神经保护性能的评估。

DESCRIPTION (provided by applicant): If scientists are to successfully address the largest biomedical challenges facing society, our ability to both identify and create functional small molecules with unique properties must improve dramatically. Natural products have long provided great starting points for such investigations given that their structures have evolved over millennia to achieve specific biochemical functions and their synthesis improves our skills. Yet, numerous classes of such structures remain untapped. The most significant of these are oligomeric natural products, compound families created in Nature from a simple building block through deliberately uncontrolled reaction pathways that chemists have never been able to temper in the laboratory. This proposal seeks to provide the innovative synthetic solutions needed to alter this paradigm and finally access these classes of molecules in a controlled manner, thus enabling exploration of their full biochemical potential. Our initial proving ground lies with the resveratrol family of natural products, an abundant class of compounds whose properties in initial screens appear perfect for a rich discovery program given their structural uniqueness and anti-tumor, anti-viral, anti-fungal, anti-oxidant, and anti-aging behavior (many by unknown or unique modes of action). Viewing these targets through the lens of a unique synthetic strategy, we show how the diverse carbogenic complexity of the entire class (along with several non-natural structures) can be assembled from a single, common building block well removed from Nature's starting material through a series of creative complexity-building sequences initiated by the simplest of reagents. These largely unexplored compounds will then be screened thoroughly and deeply in concert with collaborators to elucidate their roles in key biochemical events, especially as relates to human biology. PUBLIC HEALTH RELEVANCE: The proposal seeks to determine whether phenols in red wine, such as resveratrol and molecules derived from resveratrol, are responsible for the "French paradox." Synthesized compounds will be evaluated for anticancer, antiviral, antiaging, and neuroprotective properties.