Design, synthesis, and biological evaluation of C7-functionalized DMXAA derivatives as potential human-STING agonists†
STING, a central protein in the innate immune response to cytosolic DNA, has emerged as a hot target for the development of vaccine-adjuvants and anticancer drugs. The discovery of potent human-STING (hSTING) agonist is expected to revolutionize the current cancer immunotherapy. Inspired by the X-ray crystal structure of DMXAA (5,6-dimethylxanthenone-4-acetic acid) and hSTINGG230I complex, we designed various DMXAA derivatives that contain a hydrogen bonding donor/acceptor or a halide at the C7 position. While 7-bromo- and 7-hydroxyl-DMXAA showed notable binding to mouse-STING (mSTING), our newly synthesized C7-functionalized DMXAA derivatives did not bind to hSTING. Nevertheless, our newly developed synthetic protocol for the C7-functionalization of DMXAA would be applicable to access other C7-substituted DMXAA analogues as potential hSTING agonists.