Regarding the fact that local formation of E2 from E1S via the su

Regarding the fact that local formation of E2 from E1S via the sulfatase pathway is more effective in some hormone-dependent tumors than formation of E2 via the aromatase pathway [102], STS inhibitors offer an attractive strategy to reduce estrogenic stimulation of hormone-sensitive tumors [103]. Furthermore, high levels of STS and low SULT1E1 expression are regarded as prognostic factors in hormone-sensitive cancer, for example, of the breast. Blocking STS may Inhibitors,research,lifescience,medical therefore offer an additional benefit in the therapy, and STS inhibitors are under development [104, 105]. The first approach was to block the desulfonation of E1S by offering nonhydrolysable E1S

analogues, for example, sulfates of the flavonoid Inhibitors,research,lifescience,medical daidzein. However, these compounds possess high intrinsic estrogenic activity. Therefore, different STS inhibitors have been developed, a number of successful products

in which the sulfate moiety was replaced by a sulfamate, for example, estrone 3-o-sulfamate were introduced, and estradiol 3-sulfamate was introduced Inhibitors,research,lifescience,medical into clinical trials but failed because of the estrogenic effects of the products. To prevent the estrogenic effects, sulfamate-based nonsteroidal inhibitors were introduced, and the most successful derivate was the cyclopentane carboxylate derivative STX64 (irosustat), which is present in clinical development (Phase 2 clinical trials) for the treatment of patients with advanced Cyclopamine breast cancer and other hormone-dependent cancer. The structure is a tricyclic coumarin-based sulfamate. It undergoes desulfonylation as a result of its mechanism of STS inhibition [104]. Regarding the benefit of the therapeutic application of aromatase inhibitors and Inhibitors,research,lifescience,medical present knowledge on the importance Inhibitors,research,lifescience,medical of the inhibition of STS, compounds to inhibit both pathways (so-called DASIs) are now under investigation. They may provide a new therapeutic concept. One approach to create such DASIs is the insertion of a

pharmacophore for STS inhibition into an established aromatase inhibitor, for example, letrozole. For example, the pharmacophore for STS inhibition, a phenol sulfamate ester, and the pharmacophore for aromatase inhibition, an N-containing heterocyclic ring, are incorporated into a single molecule. Another group of DASIs comprises derivatives of a known STS inhibitor incorporating a heme-ligating heterocyclic Thalidomide ring [105]. Many of these novel inhibitors of both enzymes were found to be effective in preclinical studies. This approach offers the opportunity for further continuing preclinical development of such dual inhibitors. 6. Steroid Sulfatase as a Target for Biomedical Positron Emission Tomography Imaging Positron emission tomography (PET) is a biomedical imaging technique in which compounds labelled with positron emitting radioisotopes, for example, 11C, 18F, are applied to monitor processes in cells.

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