Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, P. R. China.
College of Pharmaceutical Science and Institute of Drug Development & Chemical Biology, Zhejiang University of Technology, Hangzhou, 310014, P. R. China.
Adv Sci (Weinh). 2022 Sep;9(26):e2202790. doi: 10.1002/advs.202202790. Epub 2022 Jul 19.
A successful DNA-encoded library (DEL) will consist of diverse skeletons and cover chemical space as comprehensive as possible to fully realize its potential in drug discovery and chemical biology. However, the lack of versatile on-DNA arylation methods for phenols that are less nucleophilic and reactive poses a great hurdle for DEL to include diaryl ether, a privileged chemotype in pharmaceuticals and natural products. This work describes the use of "substrate activation" approach to address the arylation of DNA-conjugated phenols. Diaryliodonium salt, a highly electrophilic and reactive arylation reagent, is employed as Ar sources to ensure highly selective on-DNA arylation of phenols and oximes with both high yields and DNA fidelity. Notably, the new on-DNA arylation reaction can be applied to the late-stage modification of peptides containing tyrosine side-chain and to synthesize DNA-tagged analogues of existing drug molecules such as sorafenib, a known pan-kinase inhibitor. The new on-DNA diaryliodonium salts chemistry affords a greater flexibility in DEL design and synthesis.
一个成功的 DNA 编码库（DEL）将包含多样化的骨架，并尽可能全面地涵盖化学空间，以充分发挥其在药物发现和化学生物学中的潜力。然而，对于亲核性和反应性较低的酚类化合物，缺乏多功能的 DNA 芳基化方法，这对包括二芳基醚（药物和天然产物中的一种优势结构类型）在内的 DEL 提出了巨大的挑战。本工作描述了使用“底物激活”方法来解决 DNA 连接的酚类化合物的芳基化问题。二芳基碘𬭩盐是一种高反应性的芳基化试剂，作为 Ar 源，可确保酚类化合物和肟类化合物在 DNA 上高度选择性的芳基化，具有高产率和 DNA 保真度。值得注意的是，新的 DNA 芳基化反应可应用于含有酪氨酸侧链的肽的后期修饰，并可合成现有药物分子（如索拉非尼，一种已知的泛激酶抑制剂）的 DNA 标记类似物。新的 DNA 二芳基碘𬭩盐化学为 DEL 的设计和合成提供了更大的灵活性。
