Sulfate derivatives of 2-phenylindols as novel steroid sulfatase inhibitors : an in vitro study on structure-activity-relationship

Abstract The growth of hormone-dependent mammary tumor cells is stimulated by non-conjugated estrogens. One important source of these hormones in the tumors could be the enzymatic hydrolysis of circulating estrogen sulfates by steroid sulfatase (EC 3.1.6.2). Inhibition of this enzyme may result in reduced levels of endogenous estrogens and, consequently, in a reduced proliferation rate of estrogendependent tumors. This paper reports on a series of inhibitors of steroid sulfatase based on sulfated derivatives of 2-phenylindoles, a new class of mammary tumor inhibiting compounds. Starting from hydroxy-substituted 2-phenylindoles, a number of mono- and disulfates were synthesized and tested for steroid sulfatase inhibiting properties. The enzymatic test was based on the measurement of [ 3 H]estrone formed from [ 3 H]estrone sulfate in the presence of various amounts of inhibitor. The concentrations which result in a 50% reduction of the rate of hydrolysis ( ic 50 ) were determined. Sulfates of hydroxylated 2-phenylindoles are substrates of steroid sulfatase. The most potent of these inhibitors show affinities which are comparable to the affinities of natural substrates. The test data further suggest that mono-sulfated compounds exhibit stronger enzyme-inhibiting properties than do disulfates.