Abstract
An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10). This compound is 5-fold more potent in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and exhibits a significantly longer duration of inhibition over (2). These biological properties are attributed to the increased lipophilicity and metabolic stability of (10) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg(98) in the active site of human steroid sulfatase. Like other sulfamates, (10) is expected to be sequestered, and transported by, erythrocytes in vivo because it inhibits human carbonic anhydrase II (hCAII) potently (IC(50), 3 nmol/L). A congener (4), which possesses a N-(pyridin-3-ylmethyl) substituent, is even more active (IC(50), 0.1 nmol/L). To rationalize this, the hCAII-(4) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (4) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the N-(pyridin-3-ylmethyl) group and Nepsilon(2) of Gln(136). Like (2), both (10) and its phenolic precursor (9) are non-estrogenic using a uterine weight gain assay. In summary, a highly potent, long-acting, and nonestrogenic steroid sulfatase inhibitor was designed with hCAII inhibitory properties that should positively influence in vivo behavior. Compound (10) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer.
Highlights
Endocrine therapy is an effective form of treatment for hormone-dependent breast cancer
An improved steroid sulfatase inhibitor was prepared by replacing the N-propyl group of the second-generation steroid-like inhibitor (2) with a N-3,3,3-trifluoropropyl group to give (10)
This compound is 5-fold more potent than (2) in vitro, completely inhibits rat liver steroid sulfatase activity after a single oral dose of 0.5 mg/kg, and, more interestingly, exhibits a significantly longer duration of inhibition over (2) with a 50% recovery after 17 days. These distinctive biological properties of (10) can be attributed to the increased lipophilicity and metabolic stability of the molecule rendered by its trifluoropropyl group, and the potential H-bonding between its fluorine atom(s) and Arg[98] in the active site of human steroid sulfatase, as suggested by molecular docking studies
Summary
Endocrine therapy is an effective form of treatment for hormone-dependent breast cancer. A new form of endocrine therapy is emerging clinically that would deliver estrogen deprivation via a distinct and novel mechanism. This involves the inhibition of the production of estrogenic steroids via the steroid sulfatase pathway. Dehydroepiandrosterone can be reduced by this enzyme to androstenediol, which, an androgen, can bind to the estrogen receptor and stimulate the growth of hormonedependent cancer cells in vitro and support the growth of carcinogen-induced mammary tumors in vivo in rodents (1, 2). Steroid sulfatase inhibitors, when used alone or in concert with an aromatase inhibitor, may enhance the response of hormone-dependent breast tumors to this type of endocrine therapy by reducing the formation of E1 from estrone-3-sulfate and the synthesis of other steroids with estrogenic properties such as androstenediol
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