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性质的功能性小分子的能力必须 显著提高。长期以来，天然产品一直为这种 研究认为它们的结构经过数千年的演变达到了特定的目标 生化功能及其合成提高了我们的技能。然而，为数众多的此类 这些建筑仍未被开发。其中最重要的是低聚天然产物， 自然界中由简单的建筑积木通过刻意创造的复合族 不受控制的反应途径，化学家们从未能够在实验室中驯化。 这项提议寻求提供改变这一范式所需的创新合成解决方案 最终以受控的方式访问这些类别的分子，从而使探索成为可能 它们全部的生化潜力。 我们最初的试验场是白藜芦醇天然产物家族，丰富的 一类化合物，其性质在最初的屏幕上似乎是丰富的发现的完美 由于其结构的独特性以及抗肿瘤、抗病毒、抗真菌、抗氧化、 和抗衰老行为(许多是通过未知或独特的作用模式)。查看这些目标 通过一种独特的合成策略的镜头，我们展示了不同的碳源复杂性 整个类的(连同几个非自然结构)可以从单个， 通过一系列创造性的方法，从大自然的原始材料中很好地去除了常见的积木 由最简单的试剂启动的复杂性构建序列。这些大部分都是未开发的 然后，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事件。

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.