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The Chemistry and Biology of Resveratrol-based Oligomers

白藜芦醇低聚物的化学和生物学

基本信息

批准号：
8440354
负责人：
Scott Alan Snyder
金额：
$ 30.45万
依托单位：
COLUMBIA UNIV NEW YORK MORNINGSIDE
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2015-07-31
项目状态：
已结题

项目摘要

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.

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，我们鉴定和创造具有独特性质的功能性小分子的能力必须显著改善。长期以来，天然产品为这些产品提供了很好的起点。研究，因为它们的结构已经发展了几千年，以实现特定的生物化学功能及其合成提高了我们的技能。然而，许多这样的类结构仍未开发。其中最重要的是低聚天然产物，在自然界中创造的复合家庭，从一个简单的建筑块，通过故意不受控制的反应途径，化学家们从来没有能够在实验室中调节。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可控的方式访问这些类别的分子，从而实现探索它们全部的生化潜能。我们最初的试验场在于白藜芦醇家族的天然产品，一类化合物，其性质在初步筛选中似乎非常适合丰富的发现计划鉴于其结构的独特性和抗肿瘤，抗病毒，抗真菌，抗氧化剂，和抗衰老行为（许多未知或独特的作用模式）。查看这些目标通过独特的合成策略的透镜，我们展示了不同的碳源复杂性整个类别的（沿着几个非天然结构）可以由单个，通过一系列创造性的方法，由最简单的试剂引发的复杂构建序列。这些大部分未被探索的然后，将与合作者一起对化合物进行彻底和深入的筛选，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。