The A2B adenosine receptor (A2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A2BAR blockade results in antiproliferative, anti-angiogenic, anti-metastatic, and immuno-stimulatory effects. In this study, we explored the structure-activity relationships of xanthin-8-yl-benzenesulfonamides mainly by introducing a variety of linkers and substituents attached to the sulfonamide residue. A new, convergent strategy was established which facilitated the synthesis of the target compounds. Many of the new compounds exhibited subnanomolar affinity for the A2BAR combined with high selectivity. Functional groups were introduced which will allow the attachment of dyes and other reporter groups. 8-(4-((4-(4-Bromophenyl)piperazin-1-yl)sulfonyl)phenyl)-1-propylxanthine (34, PSB-1901) was the most potent A2B-antagonist (Ki0.0835 nM, KB 0.0598 nM, human A2BAR) with >10,000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.
A2B Adenosine Receptor Antagonists with Picomolar Potency
Posted by
Christa E. Müller
on 12 09 2019
Related content
03 10 2022
< 1 minute
Calculate on the cloud
In order to increase the flexibility, access and integrability, Calculators and Predictors have...
12 05 2022
< 1 minute
Coupling stabilizers open KV1-type potassium channels
ABSTRACT: The opening and closing of voltage-gated ion channels are regulated by voltage sensors...
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Boost analytical experiments with phys-chem properties
TRY CHEMICALIZE Log in for videos & slides
13 11 2021
< 1 minute
Cheminfo Stories 2021 Virtual UGM | Enhancing Sibylla’s innovative drug discovery platform with ChemAxon
Sibylla's innovative pharmacological platform is aimed at discovering new drugs for untreatable...