Discovery of the ((diaryl)methyl)phosphonic acid derivatives as novel CD73 inhibitors

• Published in: Journal of heterocyclic chemistry Vol. 60; no. 12; pp. 1959 - 1975
• Main Authors: Yang, Wenyu, Chen, Xi, Ning, Xiangli, Deng, Jianlin, Li, Rong, Lei, Pengcheng, Wang, Yanjun, Liu, Jiayu, Zhang, Weifeng, Jiang, Yingying, Wang, Zhouyu, Yang, Lingling
• Format: Journal Article
• Language: English
• Published: HOBOKEN Wiley 01.12.2023
• Subjects: Chemistry; Chemistry, Organic; Physical Sciences; Science & Technology; ADENOSINE; TUMOR-GROWTH; POTENT
• ISSN: 0022-152X; 1943-5193
• DOI: 10.1002/jhet.4722

Ecto-nucleotidase CD73 inhibits immune function by overproducing adenosine. A series of important studies have shown that CD73 is over-expressed in many cancers, and CD73 inhibitors are promising drugs for cancer (immunotherapy). Here, we describe the structure optimization of a hit compound obtained through screening an in-house chemical library, (3-(4-(3-aminophenyl)-1H-1,2,3-triazol-1-yl)phenyl-(naphthalen-1-yl)methyl)phosphonic acid (1). A series of ((diphenylmethyl) phosphonic acid) derivatives were synthesized, and all target compounds were characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). Then structure-activity relationship analysis using the in vitro enzymatic inhibition assay was performed, which led to the discovery of a number of compounds (11, 13, 14, 17, 19, 23, and 27) that exhibited greater inhibitory activity than the lead compound 1. Among them, the compounds 14 and 23, with p-Cl and p-ethyl substitution on the terminal phenyl ring respectively, showed the strongest inhibitory activity against CD73, with IC50 values of 2.35 and 2.55 mu M respectively. And we believe that compounds 14 and 23 can serve as lead compounds for further research on specific CD73 inhibitors.