Synthesis and evaluation of adenosine derivatives as A1, A2A, A2B and A3 adenosine receptor ligands containing boron clusters as phenyl isosteres and selective A3 agonists

A series of adenosine and 2 '-deoxyadenosine pairs modified with a 1,12-dicarba-closo-dodecaborane cluster or alternatively with a phenyl group at the same position was synthesized, and their affinity was determined at A(1), A(2A), A(2B) and A(3) adenosine receptors (ARs). While AR affinity differences were noted, a general tendency to preferentially bind A(3) AR over other ARs was observed for most tested ligands. In particular, 5 '-ethylcarbamoyl-N-6-(3-phenylpropyl)adenosine (18), N-6-(3-phenylpropyl)-2-chloroadenosine (24) and N-6-(3-phenylpropyl)adenosine (40) showed nanomolar A(3) affinity (K-i 4.5, 6.4 and 7.5 nM, respectively). Among the boron cluster-containing compounds, the highest A(3) affinity (K-i 206 nM) was for adenosine derivative 41 modified at C2. In the matched molecular pairs, analogs bearing boron clusters were found to show lower binding affinity for adenosine receptors than the corresponding phenyl analogs. Nevertheless, interestingly, several boron cluster modified adenosine ligands showed significantly higher A(3) receptor selectivity than the corresponding phenyl analogs: 7 vs. 8, 15 vs. 16, 17 vs. 18. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A series of adenosine and 2'-deoxyadenosine pairs modified with a boron cluster or phenyl group showed a general tendency to preferentially bind to the A(3) adenosine receptor. Boron cluster-modified ligands exhibited higher A(3) receptor selectivity compared to phenyl analogs.