A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products.
A ring-distortion strategy to construct stereochemically complex and structurally diverse compounds from natural products.
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高通量筛选是药物发现中识别先导化合物的主要方法。因此，筛选文库的组成将在很大程度上决定可以调节的生物靶标和可以开发的治疗剂。不幸的是，大多数化合物筛选集合主要由结构或立体化学复杂性很小的平面分子组成，这些化合物不提供调节许多药物靶标所需的化学官能团的排列。在这里，我们描述了一种新的，一般的，和简易的策略，用于创建不同的化合物，具有高的结构和立体化学的复杂性，使用容易获得的天然产物作为合成的起点。我们表明，通过评估的化学性质，包括分数的sp3碳，ClogP，和立体中心的数量，这些化合物是显着更复杂和多样性比那些在标准的筛选集合，并给出了指导方针，这种策略的应用到任何合适的天然产物。
High-throughput screening is the dominant method to identify lead compounds in drug discovery. As such, the makeup of screening libraries will largely dictate the biological targets that can be modulated and the therapeutics that can be developed. Unfortunately, most compound screening collections consist principally of planar molecules with little structural or stereochemical complexity, compounds that do not offer the arrangement of chemical functionality necessary for modulation of many drug targets. Here we describe a novel, general, and facile strategy for the creation of diverse compounds with high structural and stereochemical complexity using readily available natural products as synthetic starting points. We show, through evaluation of chemical properties including fraction of sp3 carbons, ClogP, and the number of stereogenic centers, that these compounds are significantly more complex and diverse than those in standard screening collections, and guidelines are given for the application of this strategy to any suitable natural product.