The A2B adenosine receptor
(A2BAR) was proposed
as a novel target for the (immuno)therapy of cancer since A2BAR 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 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
(K
i 0.0835 nM, K
B 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.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.