A_2B Adenosine Receptor Antagonists with Picomolar Potency

The A_2B adenosine receptor (A_2BAR) was proposed as a novel target for the (immuno)therapy of cancer since A_2BAR blockade results in antiproliferative, antiangiogenic, antimetastatic, and immunostimulatory 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 A_2BAR 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 A_2B-antagonist (K_i 0.0835 nM, K_B 0.0598 nM, human A_2BAR) with >10 000-fold selectivity versus all other AR subtypes. It was similarly potent and selective at the mouse A_2BAR, making it a promising tool for preclinical studies. Computational studies predicted halogen bonding to contribute to the outstanding potency of 34.