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

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.