A(3) Adenosine Receptor Antagonists with Nucleoside Structures and Their Anticancer Activity

The overexpression of the A(3) adenosine receptor (AR) in a number of cancer cell types makes it an attractive target for tumor diagnosis and therapy. Hence, in the search for new A(3)AR ligands, a series of novel 2,N-6-disubstituted adenosines (Ados) was synthesized and tested in radioligand binding and functional assays at ARs. Derivatives bearing a 2-phenethylamino group in the N-6-position were found to exert higher A(3)AR affinity and selectivity than the corresponding N-6-(2,2diphenylethyl) analogues. 2-Chloro-N-6-phenylethylAdo (15) was found to be a potent full A(3)AR agonist with a Ki of 0.024 nM and an EC50 of 14 nM, in a cAMP accumulation assay. Unlike 15, the other ligands behaved as A(3)AR antagonists, which concentration-dependently reduced cell growth and exerted cytostatic activity on the prostate cancer cell line PC3, showing comparable and even more pronounced effects with respect to the ones elicited by the reference full agonist Cl-IB-MECA. In particular, the N-6-(2,2-diphenylethyl)-2-phenylethynylAdo (12: GI(50) = 14 mu M, TGI = 29 mu M, and LC50 = 59 mu M) showed the highest activity proving to be a potential antitumor agent. The cytostatic effect of both A(3)AR agonist (Cl-IB-MECA) and antagonists (12 and other newly synthesized com- pounds) confirm previous observations according to which, in addition to the involvement of A(3)ARs, other cellular mechanisms are responsible for the anticancer effects of these ligands.