Unusual Pharmacophores and New Tools for Cross-Coupling

“不寻常的药效团和交叉偶联的新工具”摘要，5R35GM122606 生物测定引导的细胞分级分离揭示了新的和新的受体结合的小分子。 意想不到的方式。这些细胞代谢产物从进化中出现，具有复杂的分子特征 功能预优化。高立体化学含量、高球形度和不同杂原子含量 与简单、扁平和非极性相比， 物质.大型分子库的参数化支持了进化之间的相关性， 优化和治疗设计：“药物”化学空间优化远离商业建筑 块和天然产物（NP空间）。这些类型的分子代表了对化学物质的挑战。 然而，合成需要优化和人类使用的新化学工具的开发。 这笔赠款推进了我们对NP空间的快速访问和导航的工作。我们强大 合成复杂分子的路线已经被证明是可行的：合成使我们能够注释和修改生物 功能在接下来的赠款期间，我们将这种方法扩展到三个领域。首先，我们发展 化学获得两个化学型与已知的表型效应，但未知的生物学目标。一 目标刺激了一个新的，立体选择性的交叉偶联反应的发现，而另一个 启发了将惰性支架转化为蛋白质加合的新弹头。第二，快速描述 获得已知生物靶标的复杂配体，其体现了多个生物靶标的“组合”聚集体， proteins.复杂小分子的不同结构修饰将使选择性搜索成为可能。 在这些组合靶点中，对治疗发展具有重要意义。第三，选择性 定义了双催化交叉耦合的未来目标，以达到NP空间：我们寻求解决基板 选择性、相对立体选择性和绝对立体选择性。

Abstract of “Unusual Pharmacophores and New Tools For Cross-Coupling,” 5R35GM122606 Bioassay-guided fractionation of cells uncovers small molecules that bind receptors in new and unexpected ways. These cellular metabolites emerge from evolution with complex molecular features preoptimized for function. High stereochemical content, high globularity and diverse heteroatom content impart greater specificity of protein binding and greater aqueous solubility than simple, flat and non-polar substances. Parametrization of large molecular libraries have supported a correlation between evolutionary optimization and therapeutic design: “drug” chemical space is optimized away from commercial building blocks and towards natural products (NP space). These types of molecules represent a challenge to chemical synthesis, however, and require the development of new chemical tools for optimization and human use. This grant advances our work towards the rapid access and navigation of NP space. Our robust routes to complex molecules have proven practical: synthesis allowed us to annotate and modify biological function. Over the coming grant period we extend this approach into three areas. First, we develop the chemistry to access two chemotypes with known phenotypic effects but unknown biological targets. One target has stimulated the discovery of a new, stereoselective cross-coupling reaction, whereas another has inspired the conversion of inert scaffolds to new warheads for protein adduction. Second, we describe rapid access to complex ligands of known biological targets that embody ‘combinatorial’ aggregates of multiple proteins. Diverse structural modifications of the complex small molecule will enable a search for selectivity among these combinatorial targets with consequences for therapeutic development. Third, selectivity defines the future goals of dual-catalytic cross-couplings to reach NP space: we seek to address substrate selectivity, relative stereoselectivity and absolute stereoselectivity.