Aug 2026· Journal of the American Chemical Society· 0 citations· 71 references
Abstract
Covalent probes and therapeutics must balance electrophilicity and stability for function in biological systems, yet gains in stability can sacrifice proteome coverage and limit ligand discovery. Here, we show that single-atom N-to-C substitutions of sulfonyl purines at the nucleofuge position decouple reactivity from stability. Systematic chemical proteomic profiling identifies sulfonyl-imidazopyridines as a class of electrophiles with enhanced cellular and in vivo stability while retaining tunable reactivity toward functional tyrosine and lysine sites. These electrophiles expand access to proteomic sites not engaged by parent sulfonyl-purines or related -triazoles. Importantly, the differential binding of N7- vs N9-sulfonyl-imidazopyridine regioisomer pairs expedites the discovery of proteome-wide-selective inhibitors of metabolic targets, including lanosterol synthase (LSS), phosphoglycerate mutase 1 (PGAM1), and DCTP pyrophosphatase 1 (DCTPP1). Collectively, this work establishes a general strategy for stabilizing electrophiles and introduces a platform for global ligandability mapping guided by regioselective recognition.
Sulfonyl exchange electrophiles are increasingly used in covalent probe and drug discovery, yet their intrinsic reactivity and plasma stability remain poorly defined, limiting rational warhead selection. Here we establish a systematic LC-MS framework to quantify the reactivity of sulfonyl imidazole and triazole electro...
Paramita Pal, Hannah M. Unsworth, Lyn H. Jones· Archiv der Pharmazie· 0 citations
Sulfonyl groups represent one of the most encountered structural motifs in medicinal chemistry. They serve as stable linkers that connect pharmacophoric elements within a molecule and as modulators of physicochemical properties, including lipophilicity, conformational flexibility, and metabolic susceptibility. This v...
Chen-Hui Jiang, Yi-Gang Yang, Zhi-Kun Zhang et al.· Chinese journal of chemistry· 0 citations
ABSTRACT The introduction of sulfur substituents to heterocyclic cores in fragments and drugs is hugely advantageous, improving key pharmacokinetic properties, providing additional vectors for synthetic elaboration, and potentially enhancing binding affinities. Despite this potential and their prevalence in drug discov...
Joe L Smy, Theo C Webb, Barnaby W. Greenland et al.· Angewandte Chemie· 0 citations
The sigma-1 receptor (S1R) is a chaperone protein involved in several physiological and pathological processes and represents an attractive target for the development of neuroactive and anticancer agents. Among S1R ligands, 3,3-disubstituted 3,4-dihydro-1,2,4-benzotriazines constitute a pharmacologically relevant but m...
M. Tonelli, Valeria Francesconi, Bruno Tasso et al.· Bioorganic chemistry (Print)· 0 citations
Rapid, aqueous macrocyclization strategies that proceed in high conversion are valuable for ultralarge macrocyclic peptide (MP) library synthesis via display and DNA-encoded library (DEL) technology. Here we report an on-DNA macrocyclization based on sulfur(VI) fluoride exchange (SuFEx) that unites above features. Th...
Tian-Xiong Mi, Li-Jun Fan, Amber Hackler et al.· Journal of the American Chem...· 0 citations
Vicinal bis-electrophilic halothiolcarbonates (vic-HTCs) are introduced as a platform for the chemoselective synthesis of carbohydrate carbamates under mild conditions. Their aminolysis accommodates a broad range of nucleophiles, including complex bioactive amines, providing access to glycoconjugates that remain diff...
Siwar Mejri, Khouloud Chakroun, Lamia Nakhle et al.· Journal of Organic Chemistry· 0 citations
We use cookies to run the site and, with your consent, for analytics and to show ads.
See our Cookie Policy.
