Development of subtype-selective covalent ligands for the adenosine A_2B receptor by tuning the reactive group

Abstract

Signalling through the adenosine receptors (ARs), in particular through the adenosine A2B receptor (A2BAR), has shown to play a role in a variety of pathological conditions, ranging from immune disorders...

Preparation of 18F-Labeled Tracers Targeting Fibroblast Activation Protein via Sulfur [18F]Fluoride Exchange Reaction

“…The intermediate building blocks 18 and 28 were accessed via a previously described synthetic route [ 12 , 47 ] and obtained in overall yields of 36% and 1%, respectively ( Scheme 2 A,B). The fluorosulfonation of the commercially available phenols 29 and 31 was achieved using AISF (4-(acetylamino)phenyl]imidodisulfuryl difluoride) and DBU as a base in THF to afford aryl-fluorosulfates 30 and 32 in 9% and 12% yields [ 48 ], respectively ( Scheme 2 C) [ 49 ]. Thereafter, aryl-fluorosulfates 30 and 32 were coupled with 28 using HATU and DIPEA in DMF to furnish the final compounds 12 and 13 in 46% and 43% yields, respectively.…”

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

“…The Pellecchia group then used these previous findings to develop the first Lys-covalent melanoma-IAP (ML-IAP) antagonist 360 and the first Lys-covalent BH3 peptide with high affinity and selectivity for hMcl-1. 361 There are also several case studies beyond the realm of PPI inhibitors, such as the development of Lys-covalent anthrax edema factor (EF) inhibitors based on 5′-p-fluorosulfonyl benzoyl adenosine (FSBA), 362 covalent ligands for the adenosine receptor A 2B AR 363 (further sulfonyl fluoride-bearing adenosine receptor ligands are discussed in section 5.1), and enhancement of a previous acrylate-based 364 Hsp72 inhibitor that showed a >100-fold increase in covalent binding efficiency when the warhead was switched to a sulfonyl fluoride. 365 The groups of Shoichet and Taunton used an interesting computational approach to develop lysine-targeted inhibitors for the eukaryotic translation initiation factor 4E (eIF4E).…”

“…There are also several case studies beyond the realm of PPI inhibitors, such as the development of Lys-covalent anthrax edema factor (EF) inhibitors based on 5′- p -fluorosulfonyl benzoyl adenosine (FSBA), covalent ligands for the adenosine receptor A 2B AR (further sulfonyl fluoride-bearing adenosine receptor ligands are discussed in section ), and enhancement of a previous acrylate-based Hsp72 inhibitor that showed a >100-fold increase in covalent binding efficiency when the warhead was switched to a sulfonyl fluoride …”

N-Acyl-N-Alkyl Sulfonamide Probes for Ligand-Directed Covalent Labeling of GPCRs: The Adenosine A2B Receptor as Case Study

“…d Values obtained from previous experiments. 15 to a cyanine-5 (Cy5) fluorophore, denatured, and resolved by SDS-PAGE. Ligand-directed probes 4a and 4b labeled multiple proteins at concentrations ≥ 10 nM (Figure 3A), while no concentration-dependent increase in labeling was observed for control compounds 3a and 3b (Figure 3B), indicating that the cyano substitution is necessary to enhance the electrophilicity of the N-acyl group.…”

“…These include fluorescent ligands, covalent ligands and affinity-based probes, among other types of probe molecules. − In case of the A 2B AR, there has been a recent surge in the development of chemical tools, i.e. pet tracers, − fluorescent ligands, − and covalent ligands. , These types of tool compounds, however, all occupy the orthosteric binding site of GPCR, hampering the study of GPCR signaling upon ligand-induced activation.…”