Synthesis and Biological Activity of 2,6‐Disubstituted and 2,6,9‐Trisubstituted 7‐Deazapurine Nucleobases

Abstract

High‐throughput screening of the IMTM compound library for modulatory activity on adenosine receptors (ARs) identified two deazapurine hits based on 2,6‐diaryl‐7‐deazapurines. In this study, a series of 16 new 2,6‐diaryl‐7‐deazapurine nucleobases together with four N‐9 substituted derivatives were synthesized. The synthesis was based on regioselective Suzuki cross‐coupling into position 6 followed by a second Suzuki cross‐coupling at position 2 under harsher conditions. Both cross‐couplings were performed on N‐9 protected nucleobases. Biological activity profiling identified several potent antagonists of all four subtypes of ARs and four compounds as sub‐micromolar and very selective antagonists of A3. Several final compounds showed potent in  vitro cytotoxic activity on a small panel of cancer cell lines, but with no selectivity against nonmalignant fibroblasts BJ and MRC‐5.