Wilson Rebecca M, Danishefsky Samuel J
Laboratory for Bioorganic Chemistry, Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, New York 10021, USA.
J Org Chem. 2007 Jun 8;72(12):4293-305. doi: 10.1021/jo070871s.
In this Perspective, the value of small molecule natural products (SMNPs) in the discovery of active biological agents is discussed. The usefulness of the natural products-based method of potential pharma discovery is much augmented by the capacities of chemical synthesis. The great advances in synthetic methodology allow for major editing of the natural product in the hopes of optimizing potency and therapeutic index. As a consequence of the enormous increase in the power of multistep chemical synthesis, one can now approach structures of previously impractical complexity. In constructing a plan for a multistep synthesis, two complementary thought styles are often encountered. One is the traditional and extremely powerful concept of prioritized strategic bond disconnections. The other, which we term "pattern recognition," involves the identification of moieties within the target, which are associated with reliable chemistry, and can serve to facilitate progress to the target. Recognition of such targets may require substantial recasting of the target structure to connect it to well-established types of transformations. Some of our older ventures, where ideas about pattern recognition were first being fashioned and used productively, are revisited. In addition, we provide snapshots of recently achieved total syntheses of SMNPs of novel biological potential. These vignettes serve to harmonize insights occasioned by pattern recognition, in concert with transformations enabled by the enormous growth in the power of synthesis.
在这篇观点文章中，讨论了小分子天然产物（SMNP）在发现活性生物制剂方面的价值。基于天然产物的潜在药物发现方法的实用性因化学合成能力而大大增强。合成方法学的巨大进步使得对天然产物进行重大修饰成为可能，以期优化效力和治疗指数。由于多步化学合成能力的大幅提高，现在人们能够处理以前难以实现的复杂结构。在制定多步合成计划时，通常会遇到两种互补的思维方式。一种是传统且极为强大的优先战略键断裂概念。另一种我们称之为“模式识别”，它涉及识别目标分子中与可靠化学反应相关的部分，并有助于朝着目标推进合成进程。识别此类目标可能需要对目标结构进行大量重新构建，以便将其与成熟的转化类型联系起来。我们回顾了一些早期的项目，在这些项目中，模式识别的概念首次被构思并得到有效应用。此外，我们还展示了最近完成的具有新生物潜力的小分子天然产物全合成的简要情况。这些实例有助于将模式识别带来的见解与合成能力的巨大提升所实现的转化协调起来。
