Synthesis, biological evaluation, and docking study of indole aryl sulfonamides as aromatase inhibitors

Breast cancer is the most common type of cancer in women, and two-thirds of post-menopausal breast cancer are estrogen-dependent.^[1] The estrogen production is regulated by CYP19A1 (aromatase) responsible for the conversion of androgens (C19) to estrogens (C18) by demethylation and aromatization of the steroidal A-ring.^[2] Two types of endocrine therapies are available: selective estrogen receptor modulators (SERMs) and aromatase inhibitors (AIs). AIs suppress the aromatase activity interacting with the substrate-binding site of the aromatase, and, based on their structure, were usually classified in steroidal (exemestane) and non-steroidal (letrozole and anastrozole). The third generation of AIs is the most selective and with less secondary effects compared to the previous generations.^[3]

In order to identify new aromatase enzyme inhibitors,^[4] a library of thirty aryl sulfonamide derivatives containing an indole nucleus, have been synthesized. All compounds were tested using an enzymatic assay to identify compounds with a good inhibitor activity of CYP19A1, compared to letrozole. The IC₅₀ of best ones, cell-viability and cytotoxicity on MCF7 human breast cancer cells were further evaluated.

Finally, the docking study showed that the best active compounds efficiently bound in the active site of the aromatase; high values of HBD and low levels of HBA are the principal requirement evidenced by the QSAR model.

1. J. Chan, K. Petrossian, S. Chen, J. Steroid. Biochem. Mol. Biol. 161 (2016) 73–83.
2. G. Waks, E.P. Winer, JAMA 321 (2019) 288-300.
3. A. Sychev, G.M. Ashraf, A.A. Svistunov, et al., Drug Des. Devel. Ther. 12 (2018) 1147–1156.
4. Di Matteo, A. Ammazzalorso, F. Andreoli, I. Caffa, B. De Filippis, M. Fantacuzzi, L. Giampietro, C. Maccallini, A. Nencioni, M.D. Parenti, D. Soncini, A. Del Rio, R. Amoroso, Bioorg. Med. Chem. Letters 26 (2016) 3192–3194.