A Cyclopropene Electrophile that Targets Glutathione S‐Transferase Omega‐1 in Cells

Wørmer, Gustav J.; Hansen, Bente K.; Palmfeldt, Johan; Poulsen, Thomas B.

doi:10.1002/ange.201907520

Cited by 7 publications

(2 citation statements)

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“…Next, we incorporated a higher degree of substitution on the cyclopropene via a range of 1,3-disubstituted cyclopropenes (see Figure 5 ) and evaluated – first by DFT – the effect of different groups at the C3 position; this 3-position in cyclopropenes is typically the position for introduction of diverse linker architectures with multiple applications in labeling and bioconjugation. 46 − 49 Initially, we evaluated the effect of CH 2 -linked moieties at the C3 position for compounds bearing an ester ( 11 ), an amide ( 12 ), and an ether ( 13 ). When compared to the unsubstituted cyclopropene 10 , higher activation enthalpies were found for compounds 11 and 12 ; on the contrary, for the CH 2 -linked ether derivative 13 , this barrier decreased by 0.3 kcal/mol.…”

Section: Resultsmentioning

confidence: 99%

Cycloaddition of Strained Cyclic Alkenes and Ortho-Quinones: A Distortion/Interaction Analysis

et al. 2020

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The chemistry of strained unsaturated cyclic compounds has experienced remarkable growth in recent years via the development of metal–free click reactions. Among these reactions, the cycloaddition of cyclopropenes and their analogues to ortho -quinones has been established as a highly promising click reaction. The present work investigates the mechanism involved in the cycloaddition of strained dienes to ortho -quinones and structural factors that would influence this reaction. For this purpose, we use B97D density functional theory calculations throughout, and for relevant cases, we use spin component–scaled MP2 calculations and single–point domain-based local pair natural orbital coupled cluster (DLPNO-CCSD(T)) calculations. The outcomes are analyzed in detail using the distortion/interaction model, and suggestions for future experimental work are made.

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Section: Resultsmentioning

confidence: 99%

Cycloaddition of Strained Cyclic Alkenes and Ortho-Quinones: A Distortion/Interaction Analysis

et al. 2020

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“…4,[11][12][13] As a separate area of application, many bioconjugation methods also rely on electrophilic agents with the aim of achieving selective biomolecular labelling with residue-or sequence-specific resolution. The introduction of new electrophilic motifs can therefore have broad impact and this is an area that we, 14,15 as well as many others, [16][17][18][19][20][21][22][23] have been recently pursuing.…”

Section: Introductionmentioning

confidence: 99%

A stable α-lactam reagent for bioconjugation and proteomic profiling

Mahía

Kiib

Nišavić

et al. 2022

Preprint

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Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry, constituting the anchor point for the design of targeted covalent inhibitors, the identification of novel therapeutic targets, and the development of a wide diversity of bioconjugation and proteomic profiling techniques. Naturally, there is great interest in the discovery of new types of biologically relevant electrophiles with potent action and broad applicability. For instance, the group of 3-membered N-heterocyclic compounds - such as aziridines, azirines, and oxaziridines – combine unique electronic properties and structural strain to trigger their respective potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, but, until this point, their utility within the field has been unexplored. Here, we demonstrate an α-lactam reagent that can be efficiently employed in the framework of bioconjugation and proteomic profiling. We have designed and synthesised a stable α-lactam, AM2, that is compatible with aqueous buffers, and have extensively characterised its properties and reactivity. In simple settings, AM2 was e.g. found to be reactive towards both thiols and amines, with the former reacting significantly faster. We further demonstrated that AM2 undergoes conjugation to free cysteine residues in peptides suggesting applications for bioconjugation. Interestingly, liver carboxylesterase 1 (CES1), a serine hydrolase with key roles in both endo- and xenobiotic metabolism, was found as a highly selective covalent target for AM2 in HepG2 liver cancer cells. All in all, our study constitutes the starting point for the further development of α-lactam-based electrophilic probes and exploration of their use in covalent chemical biology.

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Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway

et al. 2021

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The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (−)‐vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA‐sensing cGAS‐STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING‐TBK1 interaction.

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A Cyclopropene Electrophile that Targets Glutathione S‐Transferase Omega‐1 in Cells

Cited by 7 publications

References 50 publications

Cycloaddition of Strained Cyclic Alkenes and Ortho-Quinones: A Distortion/Interaction Analysis

Cycloaddition of Strained Cyclic Alkenes and Ortho-Quinones: A Distortion/Interaction Analysis

A stable α-lactam reagent for bioconjugation and proteomic profiling

Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS‐STING Pathway

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