α‐Lactam Electrophiles for Covalent Chemical Biology

• Published in: Angewandte Chemie International Edition Vol. 62; no. 26; pp. e202304142 - n/a
• Main Authors: Mahía, Alejandro, Kiib, Anders E., Nisavic, Marija, Svenningsen, Esben B., Palmfeldt, Johan, Poulsen, Thomas B.
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 26-06-2023
• Edition: International ed. in English
• Subjects: Activity-Based Protein Profiling; Amides; Azirines; Biology; Buffers (chemistry); Covalence; Hepatocytes; Heterocyclic Compounds; Hydrolases; Inhibitors; Lactams; Liver cancer; Metabolism; Nucleophiles; Reagents; Small Ring Systems; Hydrolases; Lactams; Inhibitors; Activity-Based Protein Profiling; Small Ring Systems
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.202304142

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.
We report here an α‐lactam electrophile that is tolerant of aqueous buffers and reacts with biologically relevant nucleophiles. Additionally, the compound efficiently targets and inhibits the serine hydrolase enzymes CES1/2 in HepG2 cells and cell lysate. The unique reactivity of α‐lactams suggests many potential applications of this new warhead‐class within covalent chemical biology.