SYNTHESIS AND SULFATASE INHIBITORY ACTIVITIES OF NONSTEROIDAL ESTRONESULFATASE INHIBITORS

About one-third of breast cancers are classified as estrogen-dependent breast cancers. In the past 10 years, numerous reports have suggested the importance of estrone sulfate and estrone sulfatase in regulating the supply of estrogens to these cancers. Estrone sulfatase inhibitor s may thus prove to be useful for the treatment of these diseases. Sev eral research groups have reported the development of estrone sulfatas e inhibitors, and estrone-3-O-sulfamate has been shown to be the most potent sulfatase inhibitor. However, a recent report indicated that es trone may be released during the inactivation of sulfatase by estrone- 3-O-sulfamate and rendered the inhibitor to be estrogenic. Therefore, there is a need for a potent non-steroidal sulfatase inhibitor that is metabolically stable, more selective, and lacking estrogenic activity . We developed a series of (p-O-sulfamoyl)-N-alkanoyl tyramines, and t hey proved to be potent estrone sulfatase inhibitors. Using human plac ental microsome as the enzyme source, the best inhibitor in this serie s, compound 18, has an IC50 of 55.8 nM. Another potent inhibitor in th is series, compound 17, exhibited time-dependent inactivation of sulfa tase when incubated at various concentrations (0.2-1.0 mu M) of the in hibitor. Estrone sulfate partially blocked the inactivation of the enz yme by the compound, indicating that the compound inactivated sulfatas e at the active site. The irreversible nature of the enzyme-inhibitor interaction was supported by irreversibility studies. Thus, (p-O-sulfa moyl) -N-alkanoyl tyramines represent a new series of non-steroidal es trone sulfatase inhibitor. Copyright (C) 1996 Elsevier Science Ltd.