Sulfur(VI) Fluoride Exchange Chemistry in Solid-Phase Synthesis of Compound Arrays: Discovery of Histone Deacetylase Inhibitors

09 February 2024, Version 1
This content is a preprint and has not undergone peer review at the time of posting.


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 ex-change (SuFEx) chemistry, exemplified by pairing phenols with aryl fluorosulfates, can be used for solid-phase synthesis of biologically active compounds. As a case study, we designed and synthesized a library of 84 hy-droxamic acid containing small molecules, providing a rich source of inhibitors with diverse selectivity pro-files across the human histone deacetylase enzyme family, which is a validated drug target. Among other dis-coveries, we identified a scaffold that furnished inhibitors of HDAC11 with exquisite selectivity in vitro and a selective inhibitor of HDAC6 that was shown to bind this target enzyme selectively over HDAC8 in cells, using cellular thermal shift assays (CETSA). Our results encourage the further use of SuFEx chemistry for the syn-thesis of diverse small molecule libraries, provides insight for future design of selective HDAC inhibitors, and show that CETSA can be applied for evaluation of cellular target engagement of HDAC inhibitors.


library synthesis
solid-phase synthesis
HDAC inhibitors

Supplementary materials

Supplementary information.
Supplementary schemes depicting the synthesis of building blocks and final compounds; figures depicting biochemical assay data, tables of the biochemical data behind the heat maps, experimental methods; chemical synthesis and compound characterization data; as well as copies of HPLC traces, 1H, 13C, and 19F NMR spectra.


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