SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization,Journal of the American Chemical Society

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SuFEx Click Chemistry Enabled Late-Stage Drug Functionalization
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2018-02-16 , DOI: 10.1021/jacs.7b12788
Zilei Liu _{1,

2} , Jie Li _{1,

2} , Suhua Li ₂ , Gencheng Li ₂ , K. Barry Sharpless ₂ , Peng Wu ₁

Affiliation

Sulfur(VI) Fluoride Exchange (SuFEx) is a new family of click chemistry transformations which relies on readily available materials to produce compounds bearing the SVI-F motif. The potential of SuFEx in drug discovery has just started to be explored. We report the first method of SuFEx chemistry for the conversion of phenolic compounds to their respective arylfluorosulfate derivatives in situ in 96-well plates. This method is compatible with automated synthesis and screening to quickly assess the biological activities of the in situ generated, crude products. Using this method, we perform late-stage functionalization of a panel of known anticancer drugs to generate the corresponding arylfluorosulfates. These in situ generated arylfluorosulfates are directly tested in a cancer-cell growth inhibition assay in parallel with their phenolic precursors. We discover three arylfluorosulfates that exhibit improved anticancer cell proliferation activities compared to their phenol precursors. Among these three compounds, the fluorosulfate derivative of Fulvestrant possesses significantly enhanced activity to down-regulate estrogen receptor (ER) expression in ER+ breast cancer cell line MCF-7 and the fluorosulfate derivative of Combretastatin A4-a general anticancer drug currently being evaluated under clinical trials-exhibits a 70-fold increase in potency in the drug resistant colon cancer cell line HT-29.

中文翻译：

SuFEx 点击化学实现后期药物功能化

硫 (VI) 氟化物交换 (SuFEx) 是一个新的点击化学转化系列，它依赖于现成的材料来生产带有 SVI-F 基序的化合物。SuFEx 在药物发现中的潜力才刚刚开始被探索。我们报告了 SuFEx 化学的第一种方法，用于在 96 孔板中原位将酚类化合物转化为其各自的芳基氟硫酸盐衍生物。该方法与自动合成和筛选兼容，可快速评估原位生成的粗产物的生物活性。使用这种方法，我们对一组已知的抗癌药物进行后期功能化，以生成相应的芳基氟硫酸盐。这些原位生成的芳基氟硫酸盐与其酚类前体在癌细胞生长抑制试验中直接进行测试。我们发现了三种芳基氟硫酸盐，与其苯酚前体相比，具有更好的抗癌细胞增殖活性。在这三种化合物中，氟维司群的氟硫酸盐衍生物具有显着增强的下调 ER+ 乳腺癌细胞系 MCF-7 中雌激素受体 (ER) 表达的活性，以及目前正在临床评估的通用抗癌药物 Combretastatin A4 的氟硫酸盐衍生物。试验显示抗药性结肠癌细胞系 HT-29 的效力增加了 70 倍。

更新日期：2018-02-16

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