The Chemistry and Biology of Resveratrol-based Oligomers

描述（由申请人提供）：如果科学家要成功地解决社会面临的最大的生物医学挑战，我们识别和创造具有独特性质的功能性小分子的能力必须显著提高。天然产物长期以来为这类研究提供了很好的起点，因为它们的结构已经进化了几千年，以实现特定的生化功能，它们的合成提高了我们的技能。然而，这类结构的许多类别仍未被开发。其中最重要的是天然低聚产物，即自然界中从简单的构建块通过故意不受控制的反应途径创造出的化合物家族，化学家们从未能够在实验室中进行调节。该提案旨在提供创新的合成解决方案，以改变这种模式，并最终以受控的方式获得这些分子类别，从而能够探索其全部生化潜力。我们最初的试验场是天然产品白藜芦醇家族，这是一类丰富的化合物，由于其结构的独特性和抗肿瘤、抗病毒、抗真菌、抗氧化和抗衰老的行为（许多是未知的或独特的作用模式），在最初的筛选中，它们的特性似乎是一个丰富的发现项目。通过独特的合成策略来观察这些目标，我们展示了整个类的不同碳复杂性（以及几种非自然结构）如何通过最简单的试剂发起的一系列创造性的复杂性构建序列，从一个单一的、常见的构建块组装而成，这些构建块从自然的起始材料中移除。然后，这些大部分未开发的化合物将与合作者一起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作用。公共健康相关性：该提案旨在确定红葡萄酒中的酚类物质，如白藜芦醇和白藜芦醇衍生的分子，是否导致了“法国悖论”。合成的化合物将评估其抗癌、抗病毒、抗衰老和神经保护特性。

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.