A Adenosine Receptor Antagonists with Picomolar Potency.

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