Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists
Electronic complementarity permits hindered butenolide heterodimerization and discovery of novel cGAS/STING pathway antagonists
复制标题
DOI：
10.1038/s41557-019-0413-8
复制
发表时间：
2020-02-10
期刊：
影响因子：
21.8
通讯作者：
Shenvi, Ryan A.
中科院分区：
文献类型：
--
作者：
Huffman, Benjamin J.;Chen, Shuming;Shenvi, Ryan A.
虽然联芳环可以很容易地通过交叉偶联形成，但它们的四面体，高分数sp（3）等价物不能。目前，对一般的附环合成的范围、机理和生物学特性进行了探索。这通过sp（3）-sp（3）偶联提供了直接进入完全桥头取代的途径，并使得能够快速进入天然产物空间。sp（3）-杂交的连接环是次级代谢物中的常见基序，并代表了过量填充合成文库的联芳基亚结构的四面体等价物。很少有方法可以用立体控制连接两个环的完全取代的碳原子。在这里，我们已经开发了一种立体选择性，异源选择性丁烯二酰亚胺偶联，表现出异常快速的C-C键形成的反应π系统的精致的互补性驱动。异源二聚化产生具有拓扑复杂性和不同主惯性矩的化合物集合。sp（3）-sp（3）连接环基序的特殊状态在高通量筛选环GMP-AMP合酶抑制剂/干扰素基因途径的刺激剂中得到证实，该筛选从250，000种化合物的领域中招募这些丁烯二酸异二聚体。这种一般的附着环耦合的驱动力确定了一个新的范式加入更广泛的天然产物化学空间，加速发现选择性的铅化合物。
Although biaryl rings can be easily formed via cross coupling, their tetrahedral, high-fraction sp(3) equivalents cannot. Now the scope, mechanism and biological profile of a general attached-ring synthesis has been probed. This provides direct access to full bridgehead substitution via sp(3)-sp(3) coupling and enables rapid entry to natural product space.sp(3)-hybridized attached-rings are common motifs in secondary metabolites and represent tetrahedral equivalents to the biaryl substructures that overpopulate synthetic libraries. Few methods are available that can link fully substituted carbon atoms of two rings with stereocontrol. Here we have developed a stereoselective, heteroselective butenolide coupling that exhibits an unusually fast rate of C-C bond formation driven by exquisite complementarity of the reacting pi systems. Heterodimerization generates a compound collection with topological complexity and diverse principal moments of inertia. The special status of the sp(3)-sp(3) attached-ring motif is demonstrated in a high-throughput screen for inhibitors of the cyclic GMP-AMP synthase/stimulator of interferon genes pathway, which recruited these butenolide heterodimers from a field of 250,000 compounds. The driving forces underlying this general attached-ring coupling identify a novel paradigm for the accession of wider natural product chemical space, accelerating the discovery of selective lead compounds.