Design and synthesis of tri-substituted pyrimidine derivatives as bifunctional tumor immunotherapeutic agents targeting both A 2A adenosine receptors and histone deacetylases

The A 2A adenosine receptor (A 2A AR) has attracted attention as an emerging immunotherapeutic target with several antagonists being evaluated in clinical trials. However, A 2A AR antagonists show limited efficacy as monotherapies. Herein, we communicate our design and synthesis of a novel series of A 2A AR/histone deacetylase (HDAC) bifunctional inhibitors, based on the core structure of the A 2A AR antagonist PBF-509 . The new compounds were designed using a pharmacophore-merging strategy and features a tri-substituted pyrimidine core. The binding affinity for A 2A AR and inhibitory activity against HDACs of all the new compounds were tested. A number of compounds exhibited nanomolar or subnanomolar activity against both targets and some showed equally potent antiproliferative activity against MC38, CT26 and HCT116 colon cancer lines compared to HDAC inhibitors SAHA and MGCD-0103 in vitro . The binding poses of compound 5a in both A 2A AR and HDAC1 were predicted by molecular docking studies. Collectively, these results suggest these tri-substituted pyrimidine derivatives are promising leads for developing A 2A AR/HDAC dual-acting compounds as novel antitumor agents.(c) 2023 Published by Elsevier B.V. on behalf of Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.