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Estrone sulfate analogs as estrone sulfatase inhibitors
1Division of Medicinal Chemistry, Graduate School of Pharmaceutical Sciences, Duquesne University, Pittsburgh, Pennsylvania 15282, USA.
Abstract:
The high serum concentration of estrone sulfate and the presence of estrone sulfatase in breast tumors constitute an important mechanism of local synthesis of estrogens in the tissue. Thus, inhibitors of estrone sulfatase may be effective in the treatment of estrogen-dependent breast cancer. In this study, we synthesized several isostructural analogs of estrone sulfate (estrone-3-methylsulfonate, estrone phosphate, 3-desoxyestradiol-3-methylenesulfonate, and 3-desoxyestrone-3-methylenesulfonate) and tested them on human placental sterylsulfatase. The results were (i) The Ki of 3-desoxyestrone-3-methylenesulfonate 12 and 3-desoxyestradiol-3-methylenesulfonate 7 are more than 100-fold higher than the Ki or KM values for estrone sulfate, (ii) As compared to estrone sulfate, the Ki value for estrone-3-methylsulfonate 2 is about 30-fold higher, while estrone phosphate 3 is bound by the sulfatase with roughly the same affinity as estrone sulfate. The results shed some light on the electronical and sterical requirements for high affinity binding to the enzyme.
Insights
Estrone sulfatase inhibitors show promise for treating estrogen-dependent breast cancer. New analogs were tested, revealing insights into enzyme binding requirements for potential drug development.
Area of Science:
- Biochemistry
- Medicinal Chemistry
- Oncology
Background:
- Estrogen synthesis in breast tumors is crucial for estrogen-dependent breast cancer.
- Estrone sulfatase plays a key role in local estrogen production within tumor tissues.
- Inhibiting estrone sulfatase is a potential therapeutic strategy for breast cancer.
Purpose of the Study:
- To synthesize and evaluate novel isostructural analogs of estrone sulfate.
- To assess the binding affinity of these analogs to human placental sterylsulfatase.
- To understand the structural and electronic factors governing high-affinity enzyme binding.
Main Methods:
- Synthesis of estrone sulfate analogs: estrone-3-methylsulfonate, estrone phosphate, 3-desoxyestradiol-3-methylenesulfonate, and 3-desoxyestrone-3-methylenesulfonate.
- Enzyme inhibition assays using human placental sterylsulfatase.
- Determination of inhibition constants (Ki) and Michaelis constants (KM).
Main Results:
- 3-desoxyestrone-3-methylenesulfonate and 3-desoxyestradiol-3-methylenesulfonate exhibited Ki values over 100-fold higher than estrone sulfate.
- Estrone-3-methylsulfonate showed a Ki approximately 30-fold higher than estrone sulfate.
- Estrone phosphate demonstrated similar binding affinity to estrone sulfate.
Conclusions:
- The synthesized analogs provide valuable information on the steric and electronic requirements for estrone sulfatase inhibition.
- Understanding these binding characteristics is essential for designing more effective estrone sulfatase inhibitors.
- This research contributes to the development of targeted therapies for estrogen-dependent breast cancer.