Synthesis, structure-activity relationships and molecular docking studies of phenyldiazenyl sulfonamides as aromatase inhibitors

The exploration of innovative aromatase inhibitors represents an important approach for the identification of new therapeutic treatments of breast cancer. In this respect, a series of phenyldiazenyl sulfonamides was designed, synthesized and tested. Compounds 3b, 3f and 5f showed an aromatase inhibition in the micromolar range and were evaluated in vitro on the human breast cancer cell line MCF7 by MIT assay, cytotoxicity assay (LDH release), cell cycle analysis and apoptosis, revealing a dose-dependent inhibition profile. In particular, 3f displayed the best reduction in terms of metabolic activity and an anti-proliferative effect on MCF7 cells, being blocked in the G1/S phase checkpoint. Moreover, computational studies were carried out to better understand at a molecular level of detail the rationale behind the effective binding to the active site of aromatase of the more active inhibitor 3f. The obtained results allow to consider this compound as an interesting lead for the development of a new class of nonsteroidal aromatase inhibitors. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

The study focused on designing phenyldiazenyl sulfonamides as aromatase inhibitors, with compound 3f showing the most promising inhibitory effects and ability to block cells at the G1/S cell cycle checkpoint. Through cell experiments and computational studies, a better understanding of the more active inhibitor 3f binding to the active site of aromatase was obtained, suggesting it as an interesting lead compound for the development of a new class of nonsteroidal aromatase inhibitors.