Compounds, compositions, and methods for treatment of androgen-mediated disease
A technology of compounds and compositions, applied in the fields of drug combination, steroids, organic chemistry, etc., can solve the problem of no cure for CRPC
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Embodiment 1
[0205] The synthesis of embodiment 1.STSi compound
[0206] Synthesis of Si-1 and Si-2: Representative syntheses of STSi compounds Si-1 and Si-2 are shown below. Estrone is converted to bistriflate (1). Selective insertion of a substituted carboxamide into the D ring affords compound (2). Removal of the triflate affords (3) and sulfamoylation of (3) affords Si-1. The synthesis of Si-2 was similar to Si-1 except that diisopropylamine was used instead of ethyl-isopropylamine. A total of 10 STSi compounds (Si-1 to Si-10) were synthesized and shown in Figure 1A and Figure 1B middle.
[0207]
[0208] Synthesis of Si-8 and Si-9: The synthesis of the STSi compound Si-8 is shown in the scheme below. Nitration of estrone provides a mixture of regioisomers (a) and (b). Reduction of compound (a) affords amine (c). Protection of the amine with tosyl chloride provides protected compound (d), which is further treated with sulfonyl chloride to provide protected oxathiazolidine d...
Embodiment 2
[0210] Embodiment 2.STSi activity research
[0211] Sensitivity of prostate cancer cells to STS inhibitors was tested using cell growth assays and clonogenic assays. Quantitative reverse transcription-PCR and Western blotting were performed to detect the expression levels of STS and AR. The expression of STS was downregulated using siRNA specific for STS. Steroid profiles including DHEA and androgens were analyzed by liquid chromatography-mass spectrometry (LC-MS). STS activity was determined by 4-methylumbelliferyl sulfate assay in a fluorescent microtiter plate reader. PSA secretion was determined by ELISA, and PSA-luciferase activity was measured by reporter gene assay. Eleven potent STS inhibitors were synthesized and characterized. The in vivo efficacy of two novel STS inhibitors was tested in a castrate-relapsed VCaP xenograft tumor model.
[0212] STS was found to be overexpressed in CRPC patients and cells. Inhibition of STS by siRNA was shown to inhibit cell growt...
Embodiment 3
[0215] Example 3. Characterization of STSi in Prostate Cancer Cells
[0216] To evaluate the ability of STSi to inhibit STS enzymatic activity, VCaP prostate cancer cells were treated with two synthetic STSis and the STS enzymatic activity was measured. Activity assays were performed as described by Wolff et al. (Anal Biochem, 2003. 318(2): p.276-284). figure 2 Both STSis were shown to significantly inhibit STS enzyme activity in a dose-dependent manner. image 3 The effect of other STSis on STS enzymatic activity in VCaP cells is shown.
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