Hansen Tobias N, Danková Daniela, Bæk Michael, Grlaš Linda, Olsen Christian A
Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Jagtvej 160, DK-2100 Copenhagen, Denmark.
JACS Au. 2024 Apr 17;4(5):1854-1862. doi: 10.1021/jacsau.4c00042. eCollection 2024 May 27.
Multistep synthesis performed on solid support is a powerful means to generate small-molecule libraries for the discovery of chemical probes to dissect biological mechanisms as well as for drug discovery. Therefore, expansion of the collection of robust chemical transformations amenable to solid-phase synthesis is desirable for achieving chemically diverse libraries for biological testing. Here, we show that sulfur(VI) fluoride exchange (SuFEx) chemistry, exemplified by pairing phenols with aryl fluorosulfates, can be used for the solid-phase synthesis of biologically active compounds. As a case study, we designed and synthesized a library of 84 hydroxamic acid-containing small molecules, providing a rich source of inhibitors with diverse selectivity profiles across the human histone deacetylase enzyme family. Among other discoveries, we identified a scaffold that furnished inhibitors of HDAC11 with exquisite selectivity in vitro and a selective inhibitor of HDAC6 that was shown to affect the acetylation of α-tubulin over histone sites H3K18, H3K27, as well as SMC3 in cultured cells. Our results encourage the further use of SuFEx chemistry for the synthesis of diverse small-molecule libraries and provide insight for future design of selective HDAC inhibitors.
在固体支持物上进行的多步合成是生成小分子文库的有力手段，可用于发现剖析生物学机制的化学探针以及药物研发。因此，拓展适用于固相合成的稳健化学转化反应的种类，对于构建用于生物学测试的化学多样性文库而言是很有必要的。在此，我们表明，以酚类与芳基氟硫酸盐配对为代表的硫（VI）氟交换（SuFEx）化学可用于生物活性化合物的固相合成。作为一个案例研究，我们设计并合成了一个包含84个含异羟肟酸小分子的文库，为人类组蛋白脱乙酰酶家族提供了丰富的具有不同选择性谱的抑制剂来源。在其他发现中，我们鉴定出了一种支架，它能在体外提供对HDAC11具有高选择性的抑制剂，以及一种HDAC6的选择性抑制剂，该抑制剂在培养细胞中显示出对α-微管蛋白乙酰化的影响超过对组蛋白位点H3K18、H3K27以及SMC3的影响。我们的结果鼓励进一步将SuFEx化学用于合成多样的小分子文库，并为未来选择性HDAC抑制剂的设计提供了思路。
