Design, Synthesis, and Anti-Tumor Activity of 4'-Thionucleosides as Potent and Selective Agonists at the Human A3 Adenosine Receptor

On the basis of potent and selective binding affinity of Cl-IB-MECA to the human A(3) adenosine receptor, its I-thioadenosine derivatives were efficiently synthesized starting from D-gulonic gamma-lactone. Among compounds tested, 2-chloro-N-6-(3-iodobenzyl)- and 2-chloro-N-6-methyl-4'-thioadenosine-5'-methyluronamides (7a and 7b) exhibited nanomolar range of binding affinity (K-i = 0.38 nM and 0.28 nM, respectively) at the human A(3)AR. These compounds showed anti-growth effects on HL-60 leukemia cell, which resulted from the inhibition of Wnt signaling pathway.