Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Journal of the American Chemical Society, 2020-06, Vol.142 (25), p.10899-10904

Ort / Verlag

United States: American Chemical Society

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (K i = 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 (K i = 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.