Development of (p-O-sulfamoyl)-N-alkanoyl-phenylalkyl amines as non-steroidal estrone sulfatase inhibitors

Estrogen levels in breast tumors of postmenopausal women are as much as 10 times higher than estrogen levels in plasma, presumably due to in situ form ation of estrogen. The major source of estrogen in breast cancer cells may be conversion of estrone sulfate to estrone by the enzyme estrone sulfatase . Thus, inhibitors of estrone sulfatase are potential agents for treatment of estrogen-dependent breast cancer. Several steroidal compounds have been developed that are potent estrone sulfatase inhibitors, most notably estron e-3-O-sulfamate. However, these compounds and their metabolites may have un desired effects, including estrogenicity. To avoid the problems associated with a potentially active steroid nucleus, we designed and synthesized a se ries of nonsteroidal estrone sulfatase inhibitors, the (p-O-surfamoyl)-N-ar kanoyl phenylalkyl amines. The compounds synthesized vary in the length of their arkanoyl chain and in the number of carbons separating the phenyl rin g and the carbonyl carbon. The ability of these compounds to inhibit estron e sulfatase activity was tested using human placental microsomes and intact cultured human breast cancer cells. Estrogenicity was also evaluated, usin g growth of estrogen-dependent human breast cancer cells. All of the test c ompounds inhibited estrone sulfatase activity of human placental microsomes to some extent, with the most effective compound having an IC50 value of 7 2 nM. In general, compounds with longer alkanoyl chains (12-14 carbons) wer e more effective than those with shorter chains. The test compounds also in hibited estrone sulfatase activity in intact cultures of MDA-MB-231 human b reast cancer cells. Again, the longer chain compounds were more effective. In both the placental and breast cancer cell sulfatase assays, the optimal distance between the phenyl ring and the carbonyl carbon was 1-2 carbons. T he MCF-7 cell proliferation assay revealed that estrone and estrone-3-O-sul famate were both estrogenic, but the (p-O-sulfamoyl)-N-alkanoyl phenylalkyl amines were not. Our data indicate the utility of (p-O-sulfamoyl)-N-alkano yl phenyl alkyl amines for inhibition of estrone sulfatase activity. Furthe rmore, our data support the concept that nonsteroidal estrone sulfatase inh ibitors map be useful as therapeutic agents for estrogen-dependent breast c ancers. (C) 1999 Elsevier Science Ltd. All rights reserved.