Chemical Synthesis and Biological Evaluation of 3-Substituted Estrone/Estradiol Derivatives as 17β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors Acting via a Reverse Orientation of the Natural Substrate Estrone

Estradiol (E2) plays an important role in the progression of diseases such as breast cancer and endometriosis. Inhibition of 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1), the enzyme that catalyzes the last step in the biosynthesis of the estrogenic hormone E2, therefore constitutes an interesting approach for the treatment of these two estrogen-dependent diseases. In order to obtain new inhibitors of 17 beta-HSD1, the impact of a m-carbamoylphenyloxy group at position three of an estrane nucleus was evaluated by preparing three derivatives of estrone (E1) and E2 using a microwave-assisted synthesis of diaryl ethers. Their inhibitory activity was addressed on two cell lines (T-47D and Z-12) representative of breast cancer and endometriosis, respectively, but unlike T-47D cells, Z-12 cells were not found suitable for testing potential 17 beta-HSD1 inhibitors. Thus, the addition of the m-carbamoylphenyl group at C3 of E1 (compound 5) did not increase the inhibition of E1 to E2 transformation by 17 beta-HSD1 present in T-47D cells (IC50 = 0.31 and 0.21 mu M for 5 and E1, respectively), and this negative effect was more obvious for E2 derivatives 6 and 10 (IC50 = 1.2 and 1.3 mu M, respectively). Molecular docking allowed us to identify key interactions with 17 beta-HSD1 and to highlight these new inhibitors' actions through an opposite orientation than natural enzyme substrate E1's classical one. Furthermore, molecular modeling experiments explain the better inhibitory activity of E1-ether derivative 5, as opposed to the E2-ether derivatives 6 and 10. Finally, when tested on T-47D and Z-12 cells, compounds 5, 6 and 10 did not stimulate the proliferation of these two estrogen-dependent cell lines. In fact, they reduced it.

Automated summary

Estradiol (E2) is crucial in the development of diseases like breast cancer and endometriosis. Inhibiting the enzyme 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1), which is responsible for the production of E2, is a promising approach for treating these estrogen-dependent diseases. This study evaluated the impact of a m-carbamoylphenyloxy group on the efficacy of estrone (E1) and E2 derivatives as inhibitors of 17 beta-HSD1, and tested their activity on breast cancer and endometriosis cell lines.