α-Lactam Electrophiles for Covalent Chemical Biology

Alejandro Mahía; Anders E Kiib; Marija Nisavic; Esben B Svenningsen; Johan Palmfeldt; Thomas B Poulsen

doi:10.1002/anie.202304142

α-Lactam Electrophiles for Covalent Chemical Biology

Alejandro Mahía, Anders E Kiib, Marija Nisavic, Esben B Svenningsen, Johan Palmfeldt, Thomas B Poulsen^*

^*Corresponding author for this work

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

7 Citations (Scopus)

13 Downloads (Pure)

Abstract

Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α-lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo- and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α-lactam-based electrophilic probes in covalent chemical biology.

Original language	English
Article number	e202304142
Journal	Angewandte Chemie - International Edition
Volume	62
Issue	26
Number of pages	11
ISSN	1433-7851
DOIs	https://doi.org/10.1002/anie.202304142
Publication status	Published - Jun 2023

Keywords

Azirines
Biology
Heterocyclic Compounds
Lactams
Inhibitors
Activity-Based Protein Profiling
Hydrolases
Small Ring Systems

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10.1002/anie.202304142Licence: CC BY-NC

Angew Chem Int Ed - 2023 - Mahía - ‐Lactam Electrophiles for Covalent Chemical BiologyFinal published version, 4.03 MBLicence: CC BY-NC

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title = "α-Lactam Electrophiles for Covalent Chemical Biology",

abstract = "Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α-lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo- and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α-lactam-based electrophilic probes in covalent chemical biology.",

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author = "Alejandro Mah{\'i}a and Kiib, {Anders E} and Marija Nisavic and Svenningsen, {Esben B} and Johan Palmfeldt and Poulsen, {Thomas B}",

year = "2023",

month = jun,

doi = "10.1002/anie.202304142",

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journal = "Angewandte Chemie - International Edition",

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AU - Mahía, Alejandro

AU - Kiib, Anders E

AU - Nisavic, Marija

AU - Svenningsen, Esben B

AU - Palmfeldt, Johan

AU - Poulsen, Thomas B

PY - 2023/6

Y1 - 2023/6

N2 - Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α-lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo- and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α-lactam-based electrophilic probes in covalent chemical biology.

AB - Electrophilic groups are one of the key pillars of contemporary chemical biology and medicinal chemistry. For instance, 3-membered N-heterocyclic compounds-such as aziridines, azirines, and oxaziridines-possess unique electronic and structural properties which underlie their potential and applicability as covalent tools. The α-lactams are also members of this group of compounds, however, their utility within the field remains unexplored. Here, we demonstrate an α-lactam reagent (AM2) that is tolerant to aqueous buffers while being reactive towards biologically relevant nucleophiles. Interestingly, carboxylesterases 1 and 2 (CES1/2), both serine hydrolases with key roles in endo- and xenobiotic metabolism, were found as primary covalent targets for AM2 in HepG2 liver cancer cells. All in all, this study constitutes the starting point for the further development and exploration of α-lactam-based electrophilic probes in covalent chemical biology.

KW - Azirines

KW - Biology

KW - Heterocyclic Compounds

KW - Lactams

KW - Inhibitors

KW - Activity-Based Protein Profiling

KW - Hydrolases

KW - Small Ring Systems

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DO - 10.1002/anie.202304142

M3 - Journal article

C2 - 37114559

SN - 1433-7851

VL - 62

JO - Angewandte Chemie - International Edition

JF - Angewandte Chemie - International Edition

IS - 26

M1 - e202304142

ER -

α-Lactam Electrophiles for Covalent Chemical Biology

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Keywords

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