Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors

Cheng, Yunfei, Li, Gencheng, Smedley, Christopher J, Giel, Marie-Claire, Kitamura, Seiya, Woehl, Jordan L, Bianco, Giulia, Forli, Stefano, Homer, Joshua A, Cappiello, John R, Wolan, Dennis W, Moses, John E, Sharpless, K Barry (September 2022) Diversity oriented clicking delivers β-substituted alkenyl sulfonyl fluorides as covalent human neutrophil elastase inhibitors. Proceedings of the National Academy of Sciences of USA, 119 (37). e2208540119. ISSN 0027-8424

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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.

Item Type:	Paper
Subjects:	bioinformatics bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification chemistry chemistry > techniques > click chemistry bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > serine proteinase inhibitors chemistry > techniques
CSHL Authors:	Homer, Joshua Moses, John E.
Communities:	CSHL Cancer Center Program CSHL labs > Moses lab CSHL Cancer Center Program > Cellular Communication in Cancer Program
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	13 September 2022
Date Deposited:	15 Sep 2022 20:49
Last Modified:	02 May 2024 13:15
PMCID:	PMC9478681
URI:	https://repository.cshl.edu/id/eprint/40717

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