Selektive Inhibition des Immunoproteasoms durch ligandeninduzierte Vernetzung des katalytischen Zentrums

Dubiella, C.; Cui, Haissi; Gersch, Malte; Brouwer, Arwin J.; Sieber, Stephan A.; Krüger, Achim; Liskamp, Rob M. J.; Groll, M.

doi:10.1002/ange.201406964

Cited by 23 publications

(2 citation statements)

References 25 publications

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“…The IC 50 values on both proteasome subunits without 30 min pre-incubation of 10e and the enzyme remained almost exactly the same indicating that this acrylamide-based inhibitor 10e was not inhibiting β5 subunits of cCP or iCP in an irreversible manner. Although the acrylamide warhead has been successfully used in covalent inhibitors very often, the absence of the covalent interaction with our compounds is most probably due to the mispositioning of the electrophilic carbon of 10e and the oxygen atom of catalytic Thr1 (in β5i and β5) or Cys48 (within the active site of β5i) (40,41). It should be noted that such an electrophilic group that is not involved in targeted covalent inhibition could be seen as a liability due to possible off-target effects.…”

Section: Biochemical Evaluationmentioning

confidence: 99%

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Gobec,

Obreza,

Jukič

et al. 2023

Acta Pharmaceutica

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The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical studies of both proteasomes.

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Section: Biochemical Evaluationmentioning

confidence: 99%

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Gobec,

Obreza,

Jukič

et al. 2023

Acta Pharmaceutica

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“…Sulfur (VI) fluoride exchange (SuFEx) click chemistry has emerged as a valuable tool in organic synthesis and biochemistry (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16). Notably, sulfamoyl fluorides have increasingly become pivotal building blocks in the SuFEx domain due to their unique properties, including chemical stability and selective reactivity at the sulfur center (1).…”

Section: Introductionmentioning

confidence: 99%

Pyridinium-based fluorosulfonamide reagents enabled photoredox catalyzed radical fluorosulfonamidation

Wang,

Li,

Zhang

et al. 2024

Preprint

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Sulfamoyl fluorides, as a crucial building block of SuFEx, have garnered extensive research interest due to their applications in chemical biology, materials science, and drug discovery. Recently, considerable research has been dedicated to the synthesis of sulfamoyl fluorides. However, the direct radical fluorosulfonamidation process for the synthesis of sulfamoyl fluorides employing fluorosulfonamide radicals has largely been overlooked. We herein disclosed a practical procedure for constructing bench-stable redox-active fluorosulfonamide radical reagent from inexpensive SO2F2, which would provide appropriate solution to the long-standing issue of radical fluorosulfonamidation. Simultaneously, the radical fluorosulfonamidating reagents, namely fluorosulfonyl-N-pyridinium tetrafluoroborate (PNSF), can be readily scaled up and prepared under simple aerobic conditions. These practical and air-stable crystalline salts can effectively facilitate a range of reactions, including the N-(fluorosulfonyl) sulfonamidation of diverse (hetero)arenes, sequential radical stereoselective fluorosulfonamidation, and the 1,2-difunctionalization of various alkenes, enabling the construction of a diverse array of functionalized sulfamoyl fluoride compounds.

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An Easy, General and Practical Method for the Construction of Alkyl Sulfonyl Fluorides

Fang

Lekkala

et al. 2020

Adv Synth Catal

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A visible light‐induced reductive addition of 1°, 2° and 3° alkyl iodides to ethenesulfonyl fluoride, employing Hantzsch ester as a hydrogen source at room temperature was developed. This method featured a wide substrate scope and great functional group compatibility, providing facile and robust process to alkyl sulfonyl fluorides including enzyme inhibitors, natural products and drugs derivatives in up to 99% yield. Further derivatization of resultant aliphatic sulfonyl fluorides was also achieved through sulfur fluoride exchange (SuFEx) reactions to deliver sulfonates and sulfonamides as privileged motifs for medicinal chemistry.magnified image

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Selektive Inhibition des Immunoproteasoms durch ligandeninduzierte Vernetzung des katalytischen Zentrums

Cited by 23 publications

References 25 publications

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

Pyridinium-based fluorosulfonamide reagents enabled photoredox catalyzed radical fluorosulfonamidation

An Easy, General and Practical Method for the Construction of Alkyl Sulfonyl Fluorides

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