Synthesis, Antiproliferative Activity, and ADME Profiling of Novel Racemic and Optically Pure Aryl-Substituted Purines and Purine Bioisosteres

The aim of this study was to synthesize new racemic and optically pure aryl-substituted purine bioisosteres using ultrasound-assisted Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition. Regioselective synthesis of α-azido alcohols was applied to afford heterocycles with a 2-hydroxyeth-1-yl linker. Catalytic asymmetric synthesis using halohydrin dehalogenase in the ring-opening of epoxides gave enantioenriched azido alcohols, which subsequently afforded <i>R</i>- and <i>S</i>-enantiomers of purine and pyrrolo[2,3-<i>d</i>]pyrimidines with a 1-hydroxyeth-2-yl linker. The newly synthesized compounds were evaluated in vitro for their antiproliferative activity against four malignant tumor cell lines. The influence of regioisomerism and the stereochemistry of the hydroxyethyl group, as well as a <i>N</i>-heterocyclic scaffold linked to the aryl moiety on cytostatic activity was evaluated. Of all the compounds tested, purine <b>40a</b> and pyrrolo[2,3-<i>d</i>]pyrimidine <b>45a</b> derivatives with <i>p</i>-trifluoromethyl-substituted aryl connected to 1,2,3-triazole via a 2-hydroxyeth-1-yl spacer showed promising submicromolar antiproliferative activity. In addition, compound <b>45a</b> exhibited selectivity towards the tumor cell line, with a selectivity index (SI) of 40, moderate clearance, and good membrane permeability.