The sulfur (VI) fluoride exchange (SuFEx) is a new family of click chemistry reactions that relies on readily available sulfuryl fluoride (SO2F2) and ethenesulfonyl fluoride (ESF) to build diverse chemical structures bearing the SVI-F motif, such as -OSO2F (fluorosulfate) and -SO2F (sulfonyl fluoride). Since the concept of SuFEx chemistry was introduced by Barry Sharpless in 2014, the studies of SuFEx chemistry in organic synthesis has significantly emerged while its values in chemical biology and medicinal chemistry was just recognized recently. Here 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.

SuFEx click chemistry enabled late-stage drug functionalization

2019 Fall National Meeting

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