德国明斯特大学Armido Studer团队研究了吲哚和苯并呋喃的碳氮原子交换和骨架编辑。2025年5月21日出版的《自然》杂志发表了这一最新研究成果。

骨架编辑包括化合物的结构重组。这种编辑可以通过原子交换、原子插入、原子删除或化合物骨架结构的重组来实现。骨架编辑是在药物开发活动的后期进行的，它使现有的药效团多样化，提高了药物开发的效率。与传统的从基本构建块构建杂芳烃不同，结构变体很容易直接从先导化合物或批准的药效团开始获得。

研究组介绍了吲哚中C2位的C到N原子交换，通过吲哚杂芳烃核的氧化裂解和随后的环闭合得到吲唑。反应通过开环肟作为中间体进行。这些环解构的中间体也可以被转移到苯并咪唑中，导致整体C到N原子交换，并伴随着骨架重组。

同样的结构转向策略同样适用于苯并呋喃，导致苯并异恶唑或苯并恶唑。通过这些方法获得的化合物类别——吲唑、苯并异恶唑、苯并咪唑和苯并恶唑——是天然产物和药物中作为亚结构发现的生物相关部分。引入的程序大大扩大了新兴骨架编辑领域的方法组合。

附：英文原文

Title: C-to-N atom swapping and skeletal editing in indoles and benzofurans

Author: Wang, Zhe, Xu, Pengwei, Guo, Shu-Min, Daniliuc, Constantin G., Studer, Armido

Issue&Volume: 2025-05-21

Abstract: Skeletal editing comprises the structural reorganization of compounds. Such editing can be achieved through atom swapping, atom insertion, atom deletion or reorganization of the compound’s backbone structure1,2. Conducted at a late stage in drug development campaigns, skeletal editing enables diversification of an existing pharmacophore, enhancing the efficiency of drug development. Instead of constructing a heteroarene classically from basic building blocks, structural variants are readily accessible directly starting from a lead compound or approved pharmacophore. Here we present C to N atom swapping in indoles at the C2 position to give indazoles through oxidative cleavage of the indole heteroarene core and subsequent ring closure. Reactions proceed through ring-opened oximes as intermediates. These ring deconstructed intermediates can also be diverted into benzimidazoles resulting in an overall C to N atom swapping with concomitant skeletal reorganization. The same structural diverting strategies are equally well applicable to benzofurans leading to either benzisoxazoles or benzoxazoles. The compound classes obtained through these methods—indazoles3,4, benzisoxazoles5, benzimidazoles6,7 and benzoxazoles8—are biologically relevant moieties found as substructures in natural products and pharmaceuticals. The procedures introduced substantially enlarge the methods portfolio in the emerging field of skeletal editing.

DOI: 10.1038/s41586-025-09019-6

Source: https://www.nature.com/articles/s41586-025-09019-6