Abstract
The 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1) catalyses the reduction of the weakly active estrone (E1) into the most potent estrogen, 17beta-estradiol (E2). E2 stimulates the growth of hormone-dependent diseases via activation of the estrogen receptors (ERs). 17beta-HSD1 is often over-expressed in breast cancer cells. Thus, it is an attractive target for the treatment of mammary tumours. The combination of a ligand- and a structure-based drug design approach led to the identification of bis(hydroxyphenyl) azoles as potential inhibitors of 17beta-HSD1. Different azoles and hydroxy substitution patterns were investigated. The compounds were evaluated for activity and selectivity with regard to 17beta-HSD2, ERalpha and ERbeta. The most potent compound is 3-[5-(4-hydroxyphenyl)-1,3-oxazol-2-yl]phenol (18, IC(50)=0.31 microM), showing very good selectivity, high cell permeability and medium CaCo-2 permeability.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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17-Hydroxysteroid Dehydrogenases / antagonists & inhibitors*
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17-Hydroxysteroid Dehydrogenases / chemistry
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Antineoplastic Agents, Hormonal / chemical synthesis
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Antineoplastic Agents, Hormonal / chemistry*
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Antineoplastic Agents, Hormonal / pharmacology*
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Azoles / chemical synthesis
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Azoles / chemistry*
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Azoles / pharmacology*
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Breast Neoplasms / drug therapy
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Breast Neoplasms / metabolism
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Caco-2 Cells
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Drug Design
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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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Estrogen Antagonists / chemical synthesis
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Estrogen Antagonists / chemistry*
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Estrogen Antagonists / pharmacology*
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Estrogens / metabolism
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Humans
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Models, Molecular
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Molecular Structure
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Permeability
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Structure-Activity Relationship
Substances
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Antineoplastic Agents, Hormonal
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Azoles
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Enzyme Inhibitors
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Estrogen Antagonists
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Estrogens
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17-Hydroxysteroid Dehydrogenases
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3 (or 17)-beta-hydroxysteroid dehydrogenase