Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia, Pennsylvania 19104-6323, United States.
Drug Discovery Science & Technology, Discovery Research & Development, AbbVie, Inc., 1 N. Waukegan Road, North Chicago, Illinois 60064-1802, United States.
J Am Chem Soc. 2022 Jul 13;144(27):12184-12191. doi: 10.1021/jacs.2c03025. Epub 2022 Jun 27.
DNA-encoded libraries have proven their tremendous value in the identification of new lead compounds for drug discovery. To access libraries in new chemical space, many methods have emerged to transpose traditional mol-scale reactivity to nmol-scale, on-DNA chemistry. However, procedures to access libraries with a greater fraction of C(sp) content are still limited, and the need to "escape from flatland" more readily on-DNA remains. Herein, we report a Giese addition to install highly functionalized bicyclo[1.1.1]pentanes (BCPs) using tricyclo[1.1.1.0]pentane (TCP) as a radical linchpin, as well as other diverse alkyl groups, on-DNA from the corresponding organohalides as non-stabilized radical precursors. Telescoped procedures allow extension of the substrate pool by at least an order of magnitude to ubiquitous alcohols and carboxylic acids, allowing us to "upcycle" these abundant feedstocks to afford non-traditional libraries with different physicochemical properties for the small-molecule products (i.e., non-peptide libraries with acids). This approach is amenable to library production, as a DNA damage assessment revealed good PCR amplifiability and only 6% mutated sequences for a full-length DNA tag.
DNA 编码文库在发现新药的新先导化合物方面已经证明了其巨大的价值。为了在新的化学空间中获取文库，已经出现了许多方法将传统的毫摩尔级反应转移到纳摩尔级、在 DNA 上的化学反应。然而，获取具有更大比例 C(sp)含量的文库的方法仍然有限，并且在 DNA 上更容易“逃离平原”的需求仍然存在。在此，我们报告了一种 Giese 加成反应，使用三环[1.1.1.0]戊烷（TCP）作为自由基连接点，从相应的卤代烃作为非稳定自由基前体，在 DNA 上安装高度官能化的双环[1.1.1]戊烷（BCP）以及其他各种烷基。缩合步骤允许将底物池扩展至少一个数量级，涵盖常见的醇和羧酸，使我们能够“回收利用”这些丰富的原料，为小分子产物提供具有不同物理化学性质的非传统文库（即，带有酸的非肽文库）。该方法适用于文库生产，因为 DNA 损伤评估显示良好的 PCR 扩增能力，并且完整 DNA 标签的突变序列仅为 6%。
