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

doi:10.1021/jacs.9b13652

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 journal › Article › peer-review

89 Scopus citations

Abstract

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 language	English (US)
Pages (from-to)	10899-10904
Number of pages	6
Journal	Journal of the American Chemical Society
Volume	142
Issue number	25
DOIs	https://doi.org/10.1021/jacs.9b13652
State	Published - Jun 24 2020
Externally published	Yes

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

Access to Document

10.1021/jacs.9b13652

Cite this

Kitamura, S., Zheng, Q., Woehl, J. L., Solania, A., Chen, E., Dillon, N., Hull, M. V., Kotaniguchi, M., Cappiello, J. R., Kitamura, S., Nizet, V., Sharpless, K. B., & Wolan, D. W. (2020). Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry. Journal of the American Chemical Society, 142(25), 10899-10904. https://doi.org/10.1021/jacs.9b13652

@article{0eb250bb9e8a4d4f8a9dbf45dac28dc4,

title = "Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry",

abstract = "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.",

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

note = "Publisher Copyright: Copyright {\textcopyright} 2020 American Chemical Society.",

year = "2020",

month = jun,

day = "24",

doi = "10.1021/jacs.9b13652",

language = "English (US)",

volume = "142",

pages = "10899--10904",

journal = "Journal of the American Chemical Society",

issn = "0002-7863",

publisher = "American Chemical Society",

number = "25",

}

TY - JOUR

T1 - Sulfur(VI) Fluoride Exchange (SuFEx)-Enabled High-Throughput Medicinal Chemistry

AU - Kitamura, Seiya

AU - Zheng, Qinheng

AU - Woehl, Jordan L.

AU - Solania, Angelo

AU - Chen, Emily

AU - Dillon, Nicholas

AU - Hull, Mitchell V.

AU - Kotaniguchi, Miyako

AU - Cappiello, John R.

AU - Kitamura, Shinichi

AU - Nizet, Victor

AU - Sharpless, K. Barry

AU - Wolan, Dennis W.

PY - 2020/6/24

Y1 - 2020/6/24

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85087094267&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85087094267&partnerID=8YFLogxK

U2 - 10.1021/jacs.9b13652

DO - 10.1021/jacs.9b13652

M3 - Article

C2 - 32479075

AN - SCOPUS:85087094267

SN - 0002-7863

VL - 142

SP - 10899

EP - 10904

JO - Journal of the American Chemical Society

JF - Journal of the American Chemical Society

IS - 25

ER -

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

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this