- SuFExable Isocyanides for Ugi Reaction: Synthesis of Sulfonyl Fluoro Peptides
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Herein, the sulfonyl fluoro isocyanides were first developed as a new type of SuFExable synthon, and they are used as building blocks in the Ugi reaction (U-4CR). The Ugi reaction was established and the substrate scope was investigated, and various sulfonyl fluoro α-amino amides and peptides could be reached in a one-step synthesis. Therefore, this protocol opens a new vision for SuFExable building blocks and click chemistry, and it also provides a distinct approach to sulfonyl fluoro peptides.
- Xu, Shuheng,Cui, Sunliang
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supporting information
p. 5197 - 5202
(2021/07/20)
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- (Chlorosulfonyl)benzenesulfonyl Fluorides - Versatile Building Blocks for Combinatorial Chemistry: Design, Synthesis and Evaluation of a Covalent Inhibitor Library
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Multigram synthesis of (chlorosulfonyl)benzenesulfonyl fluorides is described. Selective modification of these building blocks at the sulfonyl chloride function under parallel synthesis conditions is achieved. It is shown that the reaction scope includes the use of (hetero)aromatic and electron-poor aliphatic amines (e.g., amino nitriles). Utility of the method is demonstrated by preparation of the sulfonyl fluoride library for potential use as covalent fragments, which is demonstrated by a combination of in silico and in vitro screening against trypsin as a model enzyme. As a result, several inhibitors were identified with activity on par with that of the known inhibitor.
- Tolmachova, Kateryna A.,Moroz, Yurii S.,Konovets, Angelika,Platonov, Maxim O.,Vasylchenko, Oleksandr V.,Borysko, Petro,Zozulya, Sergey,Gryniukova, Anastasia,Bogolubsky, Andrey V.,Pipko, Sergey,Mykhailiuk, Pavel K.,Brovarets, Volodymyr S.,Grygorenko, Oleksandr O.
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p. 672 - 680
(2018/11/23)
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- A study of the reactivity of S(VI)-F containing warheads with nucleophilic amino-acid side chains under physiological conditions
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Sulfonyl fluorides (SFs) have recently emerged as a promising warhead for the targeted covalent modification of proteins. Despite numerous examples of the successful deployment of SFs as covalent probe compounds, a detailed exploration of the factors influencing the stability and reactivity of SFs has not yet appeared. In this work we present an extensive study on the influence of steric and electronic factors on the reactivity and stability of the SF and related SVI-F groups. While SFs react rapidly with N-acetylcysteine, the resulting adducts were found to be unstable, rendering SFs inappropriate for the durable covalent inhibition of cysteine residues. In contrast, SFs afforded stable adducts with both N-acetyltyrosine and N-acetyllysine; furthermore, we show that the reactivity of arylsulfonyl fluorides towards these nucleophilic amino acids can be predictably modulated by adjusting the electronic properties of the warhead. These trends were largely conserved when the covalent reaction occurred within a protein binding pocket. We have also obtained a crystal structure depicting covalent modification of the catalytic lysine of a tyrosine kinase (FGFR1) by the ATP analog 5′-O-3-((fluorosulfonyl)benzoyl)adenosine (m-FSBA). Highly reactive warheads were demonstrated to be unstable with respect to hydrolysis in buffered aqueous solutions, indicating that warhead reactivity must be carefully tuned to provide optimal rates of protein modification. Our results demonstrate that the reactivity of SFs complements that of more commonly studied acrylamides, and we hope that this work spurs the rational design of novel SF-containing covalent probe compounds and inhibitors, particularly in cases where a suitably positioned cysteine residue is not present.
- Mukherjee,Debreczeni,Breed,Tentarelli,Aquila,Dowling,Whitty,Grimster
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supporting information
p. 9685 - 9695
(2017/11/30)
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- Synthesis of Sulfonyl Azides via Lewis Base Activation of Sulfonyl Fluorides and Trimethylsilyl Azide
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A protocol for the efficient conversion of sulfonyl fluorides into sulfonyl azides through Lewis base activation is described. The in situ generated sulfonyl azides are efficient diazo-transfer agents, affording diazo compounds and primary azides in excellent yields.
- Barrow, Andrew S.,Moses, John E.
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supporting information
p. 1840 - 1843
(2016/07/16)
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- Design, synthesis, and evaluation of cell permeable probes for protein kinases
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We have explored a novel molecular framework with a lysine core to prepare a probe library for protein kinases. Active site-directed probes, identified through screening of the library, displayed desirable labelling properties, including target specificity, good linear response to the corresponding enzymatic activity and cell permeability. Finally, a two-stage protocol utilizing the newly developed probe with an immunoprecipitation step was successfully established to monitor intracellular Src kinase activity in RK3E-v-Src cells.
- Hsu, Yu-Ling,Yang, Chun-Chieh,Chou, Tzyy-Chao,Tai, Chih-Hsuan,Chen, Long-Yuan,Fu, Shu-Ling,Lin, Jing-Jer,Lo, Lee-Chiang
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- FLUOROSULFONYL sEH INHIBITORS
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Fluorosulfonyl-substituted sEH inhibitors are compounds represented by Formula (I): wherein R1 is selected from the group consisting of alkyl, heteroalkyi, C5-C12 cycloalkyi, C5-C12 cycloalkylalkyi, C5-C12 cycloalkylheteroalkyi, arylalkyi, arylheteroalkyi, aryl, and heteroaryl; and R1 can be substituted or unsubstituted; P1 is a primary pharmacophore; P2 is a secondary pharmacophore; P3 is a tertiary pharmacophore; and L1 and L2 are linking groups. The subscript m has a value of 0 or 1; n has a value of 0 or 1; and the compound of Formula (I) includes at least one S02F ("fluorosulfonyl") group covalently bonded thereto.
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Page/Page column 36; 37
(2015/12/30)
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