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Selective estrogen receptor modulators (SERMs) are currently in use in the hormonal therapy of breast cancer. In that respect, a new hormone-related approach is the therapeutical inhibition of steroid sulfatase (STS), which converts inactive, sulfated steroids into active hormones. We investigated the potential of 6-EO-14, a non-steroidal STS inhibitor with SERM potential. The latter compound, which exhibits a sulfamate moiety, releases the phenol derivative 8-EO-14 after the irreversible inhibition of STS. STS was inhibited by 6-EO-14 (IC50 = 0.3 μM), but not 8-EO-14, in HEK-293 cells transfected with an STS expression vector. The SERM potential of 8-EO-14 was assessed in osteoblast-like Saos-2 cells by investigating its effect on cell proliferation and on the activity of alkaline phosphatase (ALP), a specific differentiation marker. Saos-2 cell proliferation was increased by 21 % following 8-EO-14 addition (1 μM), and 8-EO-14 induced ALP activity (31 % increase at 0.1 nM) via estrogen receptor alpha (ERα) similarly to the SERM raloxifene. As compared to estradiol (E2) (100 %), the relative binding affinity of 6-EO-14 and 8-EO-14) for ERα was found to be weak (0.09 and 0.01 %, respectively). When assessed in two estrogen-dependent human breast cancer cell lines (MCF-7 and T-47D), 8-EO-14 did not support MCF-7 cell proliferation, whereas both 8-EO-14 and 6-EO-14 exhibited estrogen-like growth stimulation in T-47D cells. These two compounds were also unable to block E2-induced cell proliferation, suggesting their lack of antiestrogenic activity. Despite the known potency of 6-EO-14 as an STS inhibitor, the observed trophic activity of this new scaffold towards ERα-positive cells needs to be carefully considered prior to its potential utilization as a therapeutic agent.

Inhibiting estradiol (E2) biosynthesis through 17?-hydroxysteroid dehydrogenase type 1 (17?-HSD1) inhibitors is a promising strategy for breast cancer therapy. We have designed a non-steroidal template to mimic CC-156, a potent steroidal inhibitor of 17?-HSD1. Starting from tetrahydro-isoquinolinol hydrobromide, two representative compounds were synthesized in six chemical steps: protection of the amino group, protection of the phenol, hydrolysis of the N-protecting group Fmoc, nucleophilic substitution to introduce an ethyloxirane, phenolysis with meta or para hydroxybenzamide and the hydrolysis of the MOM protecting group. Although the compounds showed a good fit when docked in the catalytic site of the enzyme, conserving the key interactions with amino acids His221 and Ser142, observed from the crystalline structure of inhibitor CC-156 with 17?-HSD1, they weakly inhibited 17?-HSD1. However, they did not show estrogenic activity when tested in vitro, suggesting the potential of this non-steroidal template for drug design. Furthermore, the synthetic approach reported here opens a door to the preparation of additional non-steroidal mimics of E2 derivatives, which could be tested on 17?-HSD1 and others biological targets