The Chemistry and Biology of Resveratrol-based Oligomers

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特性的功能性小分子的能力必须大大提高。天然产物长期以来为此类研究提供了很好的起点，因为它们的结构已经进化了数千年，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，许多类别的这种结构仍然没有得到利用。其中最重要的是低聚天然产物，这些化合物家族是在自然界中通过化学家从未能够在实验室中调节的故意不受控制的反应途径从简单的构建模块中创建的。该提案旨在提供改变这种范式所需的创新合成解决方案，并最终以受控的方式获得这些类别的分子，从而能够探索其全部生物化学潜力。我们最初的试验场在于白藜芦醇家族的天然产物，这是一类丰富的化合物，由于其结构独特性和抗肿瘤，抗病毒，抗真菌，抗氧化和抗衰老行为（许多是未知或独特的作用模式），其在初始筛选中的性质似乎非常适合丰富的发现计划。通过一个独特的合成策略的透镜查看这些目标，我们展示了整个类（沿着与几个非天然结构）的不同carbogenic复杂性可以组装从一个单一的，共同的积木以及从大自然的起始材料通过一系列的创造性的复杂性建设序列启动最简单的试剂。然后，这些基本上未被探索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相关的作用。公共卫生相关性：该提案旨在确定红葡萄酒中的酚类物质，如白藜芦醇及其衍生分子，是否是造成“法国悖论”的原因。“合成的化合物将被评估抗癌，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.