Synthesis and biological activities of flavonoid sulfamates as steroid sulfatase inhibitors
Journal of medical pharmaceutical and allied sciences(2023)
摘要
Synthesis of potent flavonoid sulfamate inhibitors of the enzyme steroid sulfatase (STS), a topical target in treating postmenopausal women with hormone-dependent breast cancer, is described in the current article. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cells. The strategies adopted to develop STS inhibitors which, while active in vivo, are devoid of any estrogenicity that would limit their use for breast cancer therapy (e.g. estrone 3-O-sulfamate, EMATE), were broadly successful. Several molecules of flavonoid sulfamates were synthesized that potentially possess both aromatase and steroid sulfatase inhibitory properties. The isoflavane-4',7-O,O-bis-sulfamate (equol bis-sulfamate) and flavone-6,4'-O,O-bis-sulfamate were found to be the most potent inhibitors of all the flavonoid sulfamate analogs in vitro, inhibiting STS by about 99% at 0.1μM in MCF-7 cells. Some of these flavonoid sulfamates were also found to be active against both enzymes’ STS and aromatase (e.g., 5-hydroxy-7-methoxyflavone-4'-O-sulfamate, 5-hydroxy-flavone-4',7-O,O-bis-sulfamate, and 5,7-dihydroxy flavanone-4'-O-sulfamate), thus demonstrating the novel concept of a dual inhibitor. The availability of flavonoid sulfamates as STS inhibitors may enable to use of them as a therapy in the treatment of breast cancer.
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关键词
flavonoid sulfamates,inhibitors,steroid,synthesis
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