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 formation 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
estrone-3-O-sulfamate. However, these compounds and their metabolites may have undesired effects, including estrogenicity. To avoid the problems associated with a potentially active
steroid nucleus, we designed and synthesized a series of nonsteroidal
estrone sulfatase inhibitors, the (p-O-sulfamoyl)-N-alkanoyl phenylalkyl
amines. The compounds synthesized vary in the length of their alkanoyl chain and in the number of carbons separating the phenyl ring and the carbonyl
carbon. The ability of these compounds to inhibit
estrone sulfatase activity was tested using human placental microsomes and intact cultured human
breast cancer cells. Estrogenicity was also evaluated, using growth of
estrogen-dependent human
breast cancer cells. All of the test compounds inhibited
estrone sulfatase activity of human placental microsomes to some extent, with the most effective compound having an IC50 value of 72 nM. In general, compounds with longer alkanoyl chains (12-14 carbons) were more effective than those with shorter chains. The test compounds also inhibited
estrone sulfatase activity in intact cultures of MDA-MB-231 human
breast 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. The MCF-7 cell proliferation assay revealed that
estrone and
estrone-3-O-sulfamate were both estrogenic, but the (p-O-sulfamoyl)-N-alkanoyl phenylalkyl
amines were not. Our data indicate the utility of (p-O-sulfamoyl)-N-alkanoyl phenyl alkylamines for inhibition of
estrone sulfatase activity. Furthermore, our data support the concept that nonsteroidal
estrone sulfatase inhibitors may be useful as therapeutic agents for
estrogen-dependent breast
cancers.