Abstract
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.
Highlights
The growth and development of the most common form of breast malignancies, hormone-dependent breast cancer (HDBC), is promoted by the presence of oestrogenic steroids
These compounds were initially used in patients for whom tamoxifen therapy had failed, data from a number of clinical trials suggest that aromatase inhibitors (AIs) provide a more effective first-line therapy against HDBC as a result of their superior efficacy and toxicology profile.[4,5,6]. Of these AIs, there is evidence to suggest that letrozole is superior to anastrozole in suppressing oestrogen levels in breast tissue and plasma in patients with postmenopausal breast cancer.[7]. It is unclear how this difference will translate to the clinic, the Femara versus Anastrozole Clinical Evaluation (FACE) trial should help to determine whether any differences in efficacy exist between these two AIs.[8]
We previously reported three series of dual aromatase–sulfatase inhibitors (DASIs) based on different AIs: examples include, compounds 1 and 2 based on letrozole,[19,20] compound 3 based on YM511 (4),[21,22,23,24] and compound 5 based on anastrozole.[25]
Summary
The growth and development of the most common form of breast malignancies, hormone-dependent breast cancer (HDBC), is promoted by the presence of oestrogenic steroids. Third-generation aromatase inhibitors (AIs), currently finding widespread application in the clinic, comprise the nonsteroidal compounds anastrozole and letrozole, and the steroidal exemestane.[1,2,3] these compounds were initially used in patients for whom tamoxifen therapy had failed, data from a number of clinical trials suggest that AIs provide a more effective first-line therapy against HDBC as a result of their superior efficacy and toxicology profile.[4,5,6] Of these AIs, there is evidence to suggest that letrozole is superior to anastrozole in suppressing oestrogen levels in breast tissue and plasma in patients with postmenopausal breast cancer.[7] It is unclear how this difference will translate to the clinic, the Femara versus Anastrozole Clinical Evaluation (FACE) trial should help to determine whether any differences in efficacy exist between these two AIs.[8]
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