Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry

Seiya Kitamura, Qinheng Zheng, Jordan L. Woehl, Angelo Solania, Emily Chen, Nicholas Dillon, Mitchell V. Hull, Miyako Kotaniguchi, John R. Cappiello, Shinichi Kitamura, Victor Nizet, K. Barry Sharpless, Dennis W. Wolan

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Optimization of small-molecule probes or drugs is a synthetically lengthy, challenging, and resource-intensive process. Lack of automation and reliance on skilled medicinal chemists is cumbersome in both academic and industrial settings. Here, we demonstrate a high-throughput hit-to-lead process based on the biocompatible sulfur(VI) fluoride exchange (SuFEx) click chemistry. A high-throughput screening hit benzyl (cyanomethyl)carbamate (Ki = 8 μM) against a bacterial cysteine protease SpeB was modified with a SuFExable iminosulfur oxydifluoride [RN=S(O)F2] motif, rapidly diversified into 460 analogs in overnight reactions, and the products were directly screened to yield drug-like inhibitors with 480-fold higher potency (Ki = 18 nM). We showed that the improved molecule is active in a bacteria-host coculture. Since this SuFEx linkage reaction succeeds on picomole scale for direct screening, we anticipate our methodology can accelerate the development of robust biological probes and drug candidates.

Original languageEnglish (US)
Pages (from-to)10899-10904
Number of pages6
JournalJournal of the American Chemical Society
Issue number25
StatePublished - Jun 24 2020
Externally publishedYes

ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry


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