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We present here the advances achieved in the development of new sulfamoylated 4-(1-phenyl-1 H -1,2,3-triazol-4-yl)phenol derivatives as potent steroid sulfatase (STS) inhibitors for the treatment of breast cancer. Prompted by promising biological results and in silico analysis, the initial series of similar compounds were extended, appending a variety of m-substituents at the outer phenyl ring. The inhibition profiles of the newly synthesized compounds were evaluated using a radioisotope enzymatic assay and, together with the preceding reported derivatives, using a radioisotope assay in MCF-7 cells. The most active compound, 5l , demonstrated an extraordinary STS inhibitory potency in MCF-7 cells with an IC 50 value improved 5-fold compared to that of the reference Irosustat (0.21 vs 1.06 nM). The five most potent compounds were assessed in vivo in a 67NR mouse mammary gland cancer model, with 4b measured to induce up to 51% tumor growth inhibition at 50 mg/kg with no evidence of side effects and toxicity.

In the present work, we report a new class of potent steroid sulphatase (STS) inhibitors based on 6-(1-phenyl-1 H -1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate derivatives. Within the set of new STS inhibitors, 6-(1-(1,2,3-trifluorophenyl)-1 H -1,2,3-triazol-4-yl)naphthalen-2-yl sulphamate 3L demonstrated the highest activity in the enzymatic assay inhibiting the STS activity to 7.98% at 0.5 µM concentration. Furthermore, to verify whether the obtained STS inhibitors are able to pass through the cellular membrane effectively, cell line experiments have been carried out. We found that the lowest STS activities were measured in the presence of compound 3L (remaining STS activity of 5.22%, 27.48% and 99.0% at 100, 10 and 1 nM concentrations, respectively). The measured STS activities for Irosustat (used as a reference) were 5.72%, 12.93% and 16.83% in the same concentration range. Moreover, a determined IC 50 value of 15.97 nM for 3L showed that this compound is a very promising candidate for further preclinical investigations.

The purpose of this review article is to provide an overview of recent achievements in the synthesis of novel steroid sulphatase (STS) inhibitors. STS is a crucial enzyme in the biosynthesis of active hormones (including oestrogens and androgens) and, therefore, represents an extremely attractive molecular target for the development of hormone-dependent cancer therapies. The inhibition of STS may effectively reduce the availability of active hormones for cancer cells, causing a positive therapeutic effect. Herein, we report examples of novel STS inhibitors based on steroidal and nonsteroidal cores that contain various functional groups (e.g. sulphamate and phosphorus moieties) and halogen atoms, which may potentially be used in therapies for hormone-dependent cancers. The presented work also includes examples of multitargeting agents with STS inhibitory activities. Furthermore, the fundamental discoveries in the development of the most promising drug candidates exhibiting STS inhibitory activities are highlighted.

A series of fluorinated analogs based on the frameworks of 4-(1-phenyl-1 H -[1,2,3]triazol-4-yl)-phenyl sulfamates have been synthesized as steroid sulfatase (STS) inhibitors. The design of chemical structures of new potential STS inhibitors was supported by molecular docking techniques to identify potential interactions between inhibitors and amino acid residues located in the STS active site. The STS inhibitory potency was evaluated on STS isolated from human placenta. We found that compounds substituted with fluorine atom at the meta position demonstrated the highest inhibitory effects in enzymatic STS assay. The most active analog 12e - inhibited STS enzyme with the IC 50 value of 36 nM.

In the present work, we described convenient methods for the synthesis of N-thiophosphorylated 3-(4-aminophenyl)-coumarin-7-O-sulfamates as steroid sulfatase (STS) inhibitors. To design the structures of the potential STS inhibitors, molecular modeling techniques were used. A computational docking method was used to determine the binding modes of the synthesized inhibitors as well as to identify potential interactions between specified functional groups on the inhibitors and the amino acid residues present in the active site of the enzyme. The inhibitory activities of the synthesized compounds were tested in an enzymatic assay with STS isolated from a human placenta. Within the set of newly synthesized compounds, 9e demonstrated the highest inhibitory activity in the enzymatic assay with an IC 50 value of 0.201 μM (the IC 50 value of 667-COUMATE in the same test was 0.062 μM). Furthermore, we tried to verify if the obtained STS inhibitors are able to pass through the cellular membrane effectively in cell line experiments. In the course of our study, we determined the STS activity in the MCF-7 cell line after incubation in the presence of the inhibitors (at 100 nM concentration). For this evaluation, we included newly synthesized compounds 9a-g and their N-phosphorylated analogs 6a-h, whose synthesis has been previously described. We found that the lowest STS activities were measured in the presence of N-phosphorylated derivatives 6e (0.1% of STS activity) and 6f (0.2% of STS activity). The measured STS activity in the presence of 667-COUMATE (used as a reference) was 0.1%. Moreover, at concentrations up to 1 μM, the most active compounds (6e, 6f, 9b, and 9e) did not exert any toxic effects on zebrafish embryos., (© 2019 Wiley Periodicals, Inc.)