A_2B Adenosine Receptor Antagonists with Picomolar Potency

Abstract

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.

Netrin-1 reduces lung ischemia-reperfusion injury by increasing the proportion of regulatory T cells

“…A2b receptor is the primary adenosine receptor expressed in endothelial cells, dendritic cells and lymphocytes, and plays a key role in pulmonary inflammation. 32,33…”

A2B Adenosine Receptor and Cancer

“…Commercially available A 2B AR antagonists as pharmacological tools include 8-arylxanthine derivatives MRS1754 13, MRS1706 14, GS6201 18, PSB-1115 21, PSB-603 22a and PSB-0788 23. Recently, an alkylxanthine with a picomolar affinity at the human A 2B AR, PSB-1901 22b, was reported [73]. Antagonists that are in clinical trials (AB928 26, PBF-1129 and theophylline 11) will be discussed in Section 9.…”

Irreversible Antagonists for the Adenosine A2B Receptor

“…Our previous work focused on the design, synthesis, and structure-activity relationships of A 2B -selective AR antagonists as pharmacological tool compounds [18]. A milestone was the development of 1-propyl-8-(p-sulfophenyl)xanthine (PSB-1115, IV), the first watersoluble A 2B AR antagonist showing good potency, but moderate selectivity, especially in rodents [19,20].…”

“…Nevertheless, it has been useful for studying the role of the A 2B AR in vivo [21]. Based on the structure of PSB-1115, we obtained sulfonamide derivatives, e.g., PSB-603 and PSB-1901 (V and VI, see Figure 1), which displayed high potency combined with outstanding A 2B -selectivity [18,22].…”

“…Suc compounds are required and will be useful for different purposes: (i) for stabilization the isolated and purified A2BAR protein to allow crystallization and X-ray structure dete mination, and (ii) for potential therapeutic application especially in cancer (immuno)the apy resulting in long-lasting receptor blockade. [18,23]. Figure 1.…”