Abstract
Ring A halogenated 13α-, 13β-, and 17-deoxy-13α-estrone derivatives were synthesised with N-halosuccinimides as electrophile triggers. Substitutions occurred at positions C-2 and/or C-4. The potential inhibitory action of the halogenated estrones on human aromatase, steroid sulfatase, or 17β-hydroxysteroid dehydrogenase 1 activity was investigated via in vitro radiosubstrate incubation. Potent submicromolar or low micromolar inhibitors were identified with occasional dual or multiple inhibitory properties. Valuable structure-activity relationships were established from the comparison of the inhibitory data obtained. Kinetic experiments performed with selected compounds revealed competitive reversible inhibition mechanisms against 17β-hydroxysteroid dehydrogenase 1 and competitive irreversible manner in the inhibition of the steroid sulfatase enzyme.
Keywords:
17β-HSD1; Estrone; STS; aromatase; halogenations.
MeSH terms
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Aromatase / metabolism*
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology*
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Estradiol Dehydrogenases / antagonists & inhibitors*
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Estradiol Dehydrogenases / metabolism
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Estrogens / biosynthesis*
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Estrone / chemical synthesis
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Estrone / chemistry
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Estrone / pharmacology*
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Halogenation
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Humans
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Molecular Conformation
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Steryl-Sulfatase / antagonists & inhibitors*
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Steryl-Sulfatase / metabolism
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Structure-Activity Relationship
Substances
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Enzyme Inhibitors
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Estrogens
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Estrone
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Estradiol Dehydrogenases
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HSD17B1 protein, human
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Aromatase
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Steryl-Sulfatase
Grants and funding
The work of Erzsébet Mernyák in this project was supported by the János Bolyai Research Scholarship of the Hungarian Academy of Sciences and by the ÚNKP-17–4 “New National Excellence Program Of The Ministry Of Human Capacities”. This work was supported by National Research, Development and Innovation Office-NKFIH through project Országos Tudományos Kutatási Alapprogramok (OTKA) SNN 124329.