The development of potent steroid sulfatase inhibitors is an important new therapeutic strategy for the treatment of postmenopausal women with breast cancer. A series of tricyclic coumarin sulfamates were synthesized, and their inhibitory properties were examined in vitro and in vivo. In a placental microsomal assay system, 667 COUMATE emerged as the most potent inhibitor with an IC50 of 8 nM. Administration of a single dose (10 mg/kg, p.o.) of 667 COUMATE inhibited rat liver estrone sulfatase activity by 93%. 667 COUMATE was devoid of estrogenicity, as indicated by its failure to stimulate the growth of uteri in ovariectomized rats. In vivo, estrone sulfate-stimulated growth of uteri in ovariectomized rats was inhibited by 667 COUMATE. Using the nitrosomethylurea-induced mammary tumor model, we found that 667 COUMATE caused regression of estrone sulfate-stimulated tumor growth in a dose-dependent manner. The identification of 667 COUMATE as a potent steroid sulfatase inhibitor will enable the therapeutic potential of this type of therapy to be evaluated.
<div>Abstract<p>An improved steroid sulfatase inhibitor was prepared by replacing the <i>N</i>-propyl group of the second-generation steroid-like inhibitor (<b>2</b>) with a <i>N</i>-3,3,3-trifluoropropyl group to give (<b>10</b>). This compound is 5-fold more potent <i>in vitro</i>, 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 (<b>2</b>). These biological properties are attributed to the increased lipophilicity and metabolic stability of (<b>10</b>) rendered by its trifluoropropyl group and also the potential H-bonding between its fluorine atom(s) and Arg<sup>98</sup> in the active site of human steroid sulfatase. Like other sulfamates, (<b>10</b>) is expected to be sequestered, and transported by, erythrocytes <i>in vivo</i> because it inhibits human carbonic anhydrase II (hCAII) potently (IC<sub>50</sub>, 3 nmol/L). A congener (<b>4</b>), which possesses a <i>N</i>-(pyridin-3-ylmethyl) substituent, is even more active (IC<sub>50</sub>, 0.1 nmol/L). To rationalize this, the hCAII-(<b>4</b>) adduct, obtained by cocrystallization, reveals not only the sulfamate group and the backbone of (<b>4</b>) interacting with the catalytic site and the associated hydrophobic pocket, respectively, but also the potential H-bonding between the <i>N</i>-(pyridin-3-ylmethyl) group and Nε<sub>2</sub> of Gln<sup>136</sup>. Like (<b>2</b>), both (<b>10</b>) and its phenolic precursor (<b>9</b>) 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 <i>in vivo</i> behavior. Compound (<b>10</b>) and other related inhibitors of this structural class further expand the armory of steroid sulfatase inhibitors against hormone-dependent breast cancer. [Mol Cancer Ther 2008;7(8):2435–44]</p></div>
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase−sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC50: aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC50: aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC50 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
An entry from the Cambridge Structural Database, the world’s repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
Concurrent inhibition of aromatase and steroid sulfatase (STS) may provide a more effective treatment for hormone-dependent breast cancer than monotherapy against individual enzymes, and several dual aromatase-sulfatase inhibitors (DASIs) have been reported. Three aromatase inhibitors with sub-nanomolar potency, better than the benchmark agent letrozole, were designed. To further explore the DASI concept, a new series of letrozole-derived sulfamates and a vorozole-based sulfamate were designed and biologically evaluated in JEG-3 cells to reveal structure-activity relationships. Amongst achiral and racemic compounds, 2-bromo-4-(2-(4-cyanophenyl)-2-(1H-1,2,4-triazol-1-yl)ethyl)phenyl sulfamate is the most potent DASI (aromatase: IC₅₀ =0.87 nM; STS: IC₅₀ =593 nM). The enantiomers of the phenolic precursor to this compound were separated by chiral HPLC and their absolute configuration determined by X-ray crystallography. Following conversion to their corresponding sulfamates, the S-(+)-enantiomer was found to inhibit aromatase and sulfatase most potently (aromatase: IC₅₀ =0.52 nM; STS: IC₅₀ =280 nM). The docking of each enantiomer and other ligands into the aromatase and sulfatase active sites was also investigated.
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