@article{19744681b9544696a086abb92e891d8a,
title = "Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors",
abstract = "Diversity Oriented Clicking (DOC) is a discovery method geared toward the rapid synthesis of functional libraries. It combines the best attributes of both classical and modern click chemistries. DOC strategies center upon the chemical diversification of core “SuFExable” hubs—exemplified by 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs)—enabling the modular assembly of compounds through multiple reaction pathways. We report here a range of stereoselective Michael-type addition pathways from SASF hubs including reactions with secondary amines, carboxylates, 1H-1,2,3-triazole, and halides. These high yielding conjugate addition pathways deliver unprecedented β-substituted alkenyl sulfonyl fluorides as single isomers with minimal purification, greatly enriching the repertoire of DOC and holding true to the fundamentals of modular click chemistry. Further, we demonstrate the potential for biological function – a key objective of click chemistry – of this family of SASF-derived molecules as covalent inhibitors of human neutrophil elastase.",
keywords = "covalent inhibitor, Diversity Oriented Clicking, human neutrophil elastase, Michael addition, SuFEx",
author = "Yunfei Cheng and Gencheng Li and Smedley, {Christopher J.} and Giel, {Marie Claire} and Seiya Kitamura and Woehl, {Jordan L.} and Giulia Bianco and Stefano Forli and Homer, {Joshua A.} and Cappiello, {John R.} and Wolan, {Dennis W.} and Moses, {John E.} and Sharpless, {K. Barry}",
note = "Funding Information: The current work was financially supported by the National Institutes of Health R01GM117145 (K.B.S.), R35GM136286 (D.W.W.), R01GM069832 (S.F.), K99GM138758 (S.K.), T32AI7354-27 (J.L.W.), and the NCI Cancer Center Support Grant 5P30CA045508 (J.E.M.). We thank The F. M. Kirby Foundation, Sunshine Foundation, S. J. Edwards, The Starr Foundation, The Wasily Family Foundation, and La Trobe University for generous support (J.E.M.). We thank the ARC for funding (J.E.M.) (Future Fellowship; FT170100156). We thank Jie Sun and the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, for performing X-ray crystallography of compounds 2-1 and 7-11, and the X-ray Crystallography Facility, UC San Diego, for compound 4-17. We thank Dr. Suhua Li, Sun Yat-Sen University, for enlightening discussions. Funding Information: ACKNOWLEDGMENTS. The current work was financially supported by the National Institutes of Health R01GM117145 (K.B.S.), R35GM136286 (D.W.W.), R01GM069832 (S.F.), K99GM138758 (S.K.), T32AI7354-27 (J.L.W.), and the NCI Cancer Center Support Grant 5P30CA045508 (J.E.M.). We thank The F. M. Kirby Foundation, Sunshine Foundation, S. J. Edwards, The Starr Foundation, The Was-ily Family Foundation, and La Trobe University for generous support (J.E.M.). We thank the ARC for funding (J.E.M.) (Future Fellowship; FT170100156). We thank Jie Sun and the State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, for performing X-ray crystallography of compounds 2-1 and 7-11, and the X-ray Crystallography Facility, UC San Diego, for compound 4-17. We thank Dr. Suhua Li, Sun Yat-Sen University, for enlightening discussions. Publisher Copyright: Copyright {\textcopyright} 2022 the Author(s). Published by PNAS.",
year = "2022",
month = sep,
day = "13",
doi = "10.1073/pnas.2208540119",
language = "English (US)",
volume = "119",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "37",
}