Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland.
Biomolecular Screening Facility, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland.
Sci Adv. 2019 Aug 21;5(8):eaaw2851. doi: 10.1126/sciadv.aaw2851. eCollection 2019 Aug.
Macrocyclic compounds are an attractive modality for drug development, but the limited availability of large, structurally diverse macrocyclic libraries hampers the discovery of leads. Here, we describe the discovery of efficient macrocyclization reactions based on thiol-to-amine ligations using bis-electrophiles, their application to synthesize and screen large libraries of macrocyclic compounds, and the identification of potent small macrocyclic ligands. The thiol-to-amine cyclization reactions showed unexpectedly high yields for a wide substrate range, which obviated product purification and enabled the generation and screening of an 8988 macrocycle library with a comparatively small effort. X-ray structure analysis of an identified thrombin inhibitor ( = 42 ± 5 nM) revealed a snug fit with the target, validating the strategy of screening large libraries with a high skeletal diversity. The approach provides a route for screening large sub-kilodalton macrocyclic libraries and may be applied to many challenging drug targets.
大环化合物是药物开发的一种有吸引力的方式，但由于大环库的结构多样性有限，因此限制了先导化合物的发现。在这里，我们描述了基于双亲电试剂的硫醇-胺连接的高效大环化反应的发现，及其在合成和筛选大环化合物文库中的应用，并鉴定了有效的小分子大环配体。硫醇-胺环化反应在很宽的底物范围内表现出出人意料的高收率，这避免了产物的纯化，并能够以相对较小的工作量生成和筛选 8988 个大环文库。对鉴定出的凝血酶抑制剂（Ki = 42 ± 5 nM）的 X 射线结构分析表明，与靶标紧密契合，验证了用高骨架多样性筛选大文库的策略。该方法为筛选大的亚千道尔顿大环化合物文库提供了一种途径，可应用于许多具有挑战性的药物靶标。
