Open AccessSulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry
Author(s) -
Seiya Kitamura,
Qinheng Zheng,
Jordan L. Woehl,
Angelo Solania,
Emily Chen,
Nicholas Dillon,
Mitchell Hull,
Miyako Kotaniguchi,
John Cappiello,
Shinichi Kitamura,
Victor Nizet,
K. Barry Sharpless,
Dennis W. Wolan
Publication year - 2020
Publication title -
journal of the american chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.115
H-Index - 612
eISSN - 1520-5126
pISSN - 0002-7863
DOI - 10.1021/jacs.9b13652
Subject(s) - chemistry , combinatorial chemistry , small molecule , drug discovery , sulfur , fluoride , yield (engineering) , high throughput screening , nanotechnology , organic chemistry , biochemistry , inorganic chemistry , materials science , metallurgy
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)F 2 ] 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.