Unusual Pharmacophores and New Tools for Cross-Coupling

摘要 生物测定引导的细胞分离发现与新的和意想不到的受体结合的小分子 方式。这些细胞代谢物是在进化过程中产生的，具有预先优化的复杂分子特征 功能。高立体化学含量、高球状度和多种杂原子含量赋予更多 蛋白质结合的专一性和比简单、扁平和非极性物质更大的水溶解性。 大分子文库的参数化支持了进化优化之间的相关性 和治疗设计：“药物”化学空间被优化，远离商业积木，朝着 自然产物(NP空间)。然而，这些类型的分子代表着对化学合成的挑战， 并要求开发新的化学工具，以供优化和人类使用。 这笔赠款推动了我们在NP空间的快速访问和导航方面的工作。我们的强健路线 复杂的分子已被证明是可行的：合成使我们能够注释和修改生物功能。 在即将到来的赠款期间，我们将这一方法扩展到三个领域。首先，我们把化学发展成 访问两种具有已知表型效应但未知生物靶标的化学类型。一个目标已经 激发了一种新的立体选择性交叉偶联反应的发现，而另一种激发了 将惰性支架转化为新的弹头以进行蛋白质吸收。其次，我们描述了快速访问 已知生物靶标的复杂配体，体现了多种蛋白质的“组合”聚集体。 复杂小分子的不同结构修饰将使人们能够在这些化合物中寻找选择性 组合靶点及其对治疗发展的影响。第三，选择性定义了未来 双催化交叉偶联达到NP空间的目标：我们寻求解决底物选择性，相对 立体选择性和绝对立体选择性。

Abstract 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.