Synthesis, Characterization, and Studies of Novel Spirooxindole Derivatives as Ecto-5'-Nucleotidase Inhibitors.

Ecto-5'-nucleotidase (ecto-5'-NT, CD73) inhibitors are promising drug candidates for cancer therapy. Traditional efforts used to inhibit the ecto-5'-nucleotidase have involved antibody therapy or development of small molecule inhibitors that can mimic the acidic and ionizable structure of adenosine 5'-monophosphate (AMP). Herein, we report an efficient, environment friendly route for the synthesis of non-nucleotide based small molecules, i.e., substituted spirooxindole derivatives - and investigated their inhibitory potential on human and rat recombinant ecto-5'-nucleotidase isozymes. These attempts have resulted in the identification of compound (IC = 0.15 ± 0.02 μM) inhibitor on -ecto-5'-NT which showed 280-fold higher inhibition and compound (IC ± 0.19 ± 0.03 μM) on -ecto-5'-NT with 406-fold enhanced inhibition than reference standard sulfamic acid. Moreover, studies were carried out to assess binding interactions of potent compounds within enzyme active sites and demonstrated excellent correlation with the experimental findings.