Identification of a series of tetrahydroisoquinoline derivatives as potential therapeutic agents for breast cancer

Abstract A series of tetrahydroisoquinoline- N -phenylamide derivatives were designed, synthesized, and tested for their relative binding affinities, and antagonistic activities against estrogen receptor (ER). Compound 1f (relative binding affinity, RBA = 5) showed higher binding affinity than tamoxifen (RBA=1), a potent ER antagonist and currently being used for breast cancer therapy. Compound 1f also exerted optimal antagonistic activity against ER in reporter and cell proliferation assays. Interestingly, compound 1j , which only has a minor agonistic effect against ER, acted as a progesterone receptor (PR) antagonist and exerted agonistic activity against AP-1 through ER pathway. Our results show that these new compounds can be employed as leading pharmacophore for further development of potent selective ER and/or PR modulators or antagonists.