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A-ring-substituted estrogen-3-O-sulfamates: potent multitargeted anticancer agents.
Mathew P Leese1, Hatem A M Hejaz, Mary F Mahon
1Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, U.K.
Journal of Medicinal Chemistry
|August 5, 2005
Summary
New anticancer drugs, 2-substituted estradiol 3-O-sulfamates (EMATEs), show potent antiproliferative and anti-angiogenic activities. The most active compound, 2-ethylestradiol-3-O-sulfamate, is 80-fold more potent than 2-methoxyestradiol.
Area of Science:
- Medicinal Chemistry
- Oncology
- Organic Synthesis
Background:
- Estradiol derivatives are explored for anticancer properties.
- Sulfamate-based modifications can enhance drug efficacy.
- Steroid sulfatase (STS) is a target in hormone-dependent breast cancer.
Purpose of the Study:
- To develop novel 2-substituted estradiol and EMATE derivatives.
- To evaluate their antiproliferative and anti-angiogenic activities.
- To assess their potential as multimechanism anticancer agents.
Main Methods:
- Directed ortho-lithiation for synthesis of 2-substituted estrone, estradiol, and EMATEs.
- In vitro assays using human cancer cell lines.
- In vitro angiogenesis inhibition assays.
- Steroid sulfatase (STS) inhibition assays.
- In vivo studies including NCI hollow fiber assay and xenograft mouse model.
Main Results:
- Efficient synthesis of various 2-substituted EMATEs achieved.
- 2-Substituted EMATEs demonstrated significant antiproliferative activity against cancer cell lines.
- 2-Ethylestradiol-3-O-sulfamate showed 80-fold greater activity than 2-methoxyestradiol.
- Compounds inhibited angiogenesis and steroid sulfatase (STS).
- In vivo studies confirmed good anticancer activity.
Conclusions:
- Novel 2-substituted EMATEs are potent anticancer agents.
- These compounds exhibit multimechanism activity, targeting proliferation, angiogenesis, and STS.
- 2-Ethylestradiol-3-O-sulfamate is a promising lead compound for further development.