Design and Synthesis of 2,6-Disubstituted-4′-Selenoadenosine-5′-N,N-Dimethyluronamide Derivatives as Human A3 Adenosine Receptor Antagonists

Abstract

A new series of 4′-selenoadenosine-5′-N,N-dimethyluronamide derivatives as highly potent and selective human A3 adenosine receptor (hA3AR) antagonists, is described. The highly selective A3AR agonists, 4′-selenoadenosine-5′-N-methyluronamides were successfully converted into selective antagonists by adding a second N-methyl group to the 5′-uronamide position. All the synthesized compounds showed medium to high binding affinity at the hA3AR. Among the synthesized compounds, 2-H-N6-3-iodobenzylamine derivative 9f exhibited the highest binding affinity at hA3AR. (Ki = 22.7 nM). The 2-H analogues generally showed better binding affinity than the 2-Cl analogues. The cAMP functional assay with 2-Cl-N6-3-iodobenzylamine derivative 9l demonstrated hA3AR antagonist activity. A molecular modelling study suggests an important role of the hydrogen of 5′-uronamide as an essential hydrogen bonding donor for hA3AR activation.

Organoselenium Compounds: Chemistry and Applications in Organic Synthesis

“…Moreover, 4′‐selenonucleoside 563 shows more effective inhibition of MCP‐1 induced microglial chemotaxis than 561 or 562 (Figure 8). [423,424] …”

“…Despite not presenting the Northern geometry 8). [423,424] Based on theoretical calculations of the electron-induced dissociation of the electrophilic 5-substituted uracils, 5-selenocyanatouracil ( 564) was directly prepared from uracil. The key reaction involved in situ formation of selenocyanogen chloride that is obtained by reaction of potassium selenocyanate with chlorine present in a chlorine-saturated glacial acetic solution resulting in the title compound 564 as shown in Scheme 107.…”