Abstract
A series of new arylamide derivatives possessing terminal sulfonate or sulfamate moieties was designed and synthesized. The target compounds were tested for in vitro inhibitory effects against the steroid sulfatase (STS) enzyme in a cell-free assay system. The free sulfamate derivative 1j was the most active. It inhibited the enzymatic activity by 72.0% and 55.7% at 20μM and 10μM, respectively. Compound 1j was further tested for STS inhibition in JEG-3 placental carcinoma cells with high STS enzyme activity. It inhibited 93.9% of the enzyme activity in JEG-3 placental carcinoma cells at 20μM with an efficacy near to that of the well-established drug STX64 as reference. At 10μM, 1j inhibited 86.1% of the STS activity of JEG-3. Its IC50 value against the STS enzyme in JEG-3 cells was 0.421μM. Thus, 1j represents an attractive new non-steroidal lead for further optimization.
Highlights
The steroid sulfatase (STS) enzyme catalyzes the hydrolysis of inactive sulfate metabolites such as estrone sulfate and dehydroepiandrosterone sulfate to the more active estrone and dehydroepiandrosterone, respectively
The target compounds 1a–m were synthesized via the pathway illustrated in Scheme 1. 4-Aminophenol (2) was reacted with cyclohexanecarbonyl chloride (3a) or cyclopentanecarbonyl chloride (3b) in the presence of anhydrous potassium carbonate to afford the phenolic intermediates 4a,b
They were tested for STS inhibitory effects against JEG-3 lysate
Summary
The steroid sulfatase (STS) enzyme catalyzes the hydrolysis of inactive sulfate metabolites such as estrone sulfate and dehydroepiandrosterone sulfate to the more active estrone and dehydroepiandrosterone, respectively. Adiol is about 100 times weaker than estradiol,[2,3,4,5] with lower affinity for the estrogen receptor.[6] the Adiol concentration in the circulation is 100-fold higher than estradiol This led to speculation that it might be equipotent to estradiol.[7] In addition, the STS pathway produces a significant amount of estrogen besides that produced by aromatase, the enzyme which catalyzes the aromatization of androgen to estrogen. The coumarin sulfamate derivative STX64 (Irosustat, 667 COUMATE, Fig. 1) has been the most potent and successful STS inhibitor to date It is currently being investigated in clinical trials for treatment of estrogen-dependent breast cancer, and has been trialed in endometrial cancer and prostate cancer.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
