Discovery of dihydrobetulinic acid as a potent small molecule CD73 inhibitor

Betulinic acid (BA) is a pentacyclic triterpene compound with various biological activities. Herein, we designed and synthesized a series of dihydrobetulinic acid (DHBA) and its derivatives for the discovery of potent ecto-5'-nucleotidase (CD73) inhibitors. Biological evaluation of DHBA and its derivatives led to the disclosure of three active compounds DHBA, ZM792 and ZM905. Further investigation of antitumor immunity revealed that DHBA could effectively restore the function of CD4⁺ T cells. These results provide novel insights for future endeavors in developing novel agents derived from natural product targeting CD73 enzyme.