Steroid sulfatase inhibitors

Rationaie for the Use of Steroid Sulfatase Inhibitors in Cancer Treatment 

The biologically inactive estrone sulfate (EIS) and dehydro-epiandrosterone-sulfate (DHEAS) are the most abundant circulating estrogenic precursors in the plasma of post-menopausal women [103]. Desulfation of inactive steroid-3-0-sulfates by estrone-sulfatase (STS) plays a key role in the regulation of levels of receptor-active estrogenic steroids (estradiol and androstenediol) in breast cancer cells (Fig. 9). There is strong evidence suggesting that estrone sulfatase (STS) and DHEA-sulfatase are the same enzyme [103]. 

The available information on the pharmacology of STS inhibitors is restricted to a few in vitro and in vivo models. From all steroidal compounds, the irreversible inhibitor EMATE was found to be the most potent STS inhibitor with an IC50 of 65 pM [ 107]. However, it has been proposed that the sulfamate moiety of EMATE irreversibly binds to the active site and releases the steroidal backbone estrone. This means that EMATE, although a potent inhibitor of STS, counteracts its own effect by releasing estrone. The most potent derivative from a series of sulfamoyloxy-substituted stilbenes inhibited the growth of MCF-7 breast cancer cells with an IC50 value of 13 nM [111]. 

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Tosyliminothiochromone-2-carboxylates 585 are inhibitors of interleukin-1 and are thus useful for the treatment of rheumatoid arthritis, multiple sclerosis, diabetes mellitus, atherosclerosis and septic shock <1995WO9514670>, and thiochromones possessing a sulfamoyloxy side chain at either C-6 or C-7 behave as steroid sulfatase inhibitors < 1999W O9952890>. 

Lapierre, J. Ahmed, V. Chen, M.-J. Ispahany, M. GuiUemette, J.G. Taylor, S.D. The difluoromethylene group as a replacement for the labile oxygen in steroid sulfates a new approach to steroid sulfatase inhibitors. Bioorg. Med. Chem. Lett. 2004, 14, 151-155. 

A. Purohit, G. J. Williams, N. M. Howarth, B. V. L. Potter, M. J. Reed, Inactivation of Steroid Sulfatase by an Active Site-Directed Inhibitor, Estrone-3-O-sulfamate , Biochemistry 1995, 34, 11508- 11514. 

The number of mammary fibroadenomas per animal (multiplicity) and incidence was significantly decreased in 625 (15/50) and 1,250 ppm (7/50) BP-exposed female F344 rats compared with controls (27/50 ppm) (Rhodes et al. 2007). In addition, the incidence of mammary fibroadenomas in the 1,250 ppm group was less than half of that predicted by the historical controls firom dietary (feed) studies. Mammary fibroadenomas are a common spontaneous neoplasm in female rats. The authors note that other BP-based compounds have been identified as inhibitors of the steroid sulfatase, an enzyme that plays a role in the synthesis of estrone and conversion to estradiol. However, the actual mechanism by which BP or its metabolites may have reduced mammary tumor incidences in these cancer bioassays is not known. 

Sulfamates (0-substituted-, N-substituted-, or di-/tri-substituted derivatives of sulfamic acid) have been used in the design of many types of therapeutic agents such as antibiotics, nucleoside/nucleotide human immunodeficiency virus (HTV) reverse transcriptase inhibitors, HIV protease inhibitors (Pis), anti-cancer drugs (steroid sulfatase and carbonic anhydrase inhibitors), anti-epileptic drugs, and weight loss drugs. 

Enzyme-catalysed desulfuration of steroids plays an important role in steroid biosynthesis and may provide a source of steroids in the growth and proliferation of breast cancer. Inhibition studies of estrone sulfatase with both steroidal and non-steroidal phosphate compounds have now shown that the best inhibitors contain phosphate mono anions and that the basic structure for inhibition does not require the steroid nucleus. ... 

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