DNA-encoded libraries (DELs) are attracting attention as a screening tool in the early stages of drug discovery. In the development of DELs, drug candidate compounds are chemically synthesized on barcode DNA. Therefore, it is important to perform the synthesis under mild conditions so as to not damage the DNA. On the other hand, coumarins are gaining increasing research focus not only because they possess excellent fluorescence properties, but also because many medicines contain a coumarin skeleton. Among the various reactions developed for the synthesis of coumarins thus far, Knoevenagel condensation followed by intramolecular cyclization under mild conditions can yield coumarins. In this study, we developed a new synthetic method for preparing a coumarin-conjugated oligonucleotide library via Knoevenagel condensation. The results showed that coumarins substituted at the 5-, 6-, 7-, or 8-positions could be constructed on DNA to afford a total of 26 coumarin-conjugated DNAs. Moreover, this method was compatible with enzymatic ligation, demonstrating its utility in DEL synthesis. The developed strategy for the construction of coumarin scaffolds based on Knoevenagel condensation may contribute to the use of DELs in drug discovery and medicinal chemistry.

DNA 编码文库 (DEL) 作为药物发现早期阶段的筛选工具而引起人们的关注。在 DEL 的开发中，候选药物化合物是在条形码 DNA 上化学合成的。因此，重要的是在温和条件下进行合成，以免损伤DNA。另一方面，香豆素越来越受到研究关注，不仅因为它们具有优异的荧光特性，而且因为许多药物都含有香豆素骨架。在迄今为止开发的用于合成香豆素的各种反应中，克诺文格尔缩合然后在温和条件下进行分子内环化可以产生香豆素。在这项研究中，我们开发了一种新的合成方法，通过Knoevenagel 缩合制备香豆素缀合的寡核苷酸文库。结果表明，在 5、6、7 或 8 位取代的香豆素可以在 DNA 上构建，以提供总共 26 个香豆素缀合的 DNA。此外，该方法与酶连接兼容，证明了其在 DEL 合成中的实用性。基于 Knoevenagel 缩合构建香豆素支架的开发策略可能有助于 DEL 在药物发现和药物化学中的使用。