Synthesis and structure-activity relationships of 2- and/or 4-halogenated 13β- and 13α-estrone derivatives as enzyme inhibitors of estrogen biosynthesis

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-hydroxy...

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Published inJournal of enzyme inhibition and medicinal chemistry Vol. 33; no. 1; pp. 1271 - 1282
Main Authors Bacsa, Ildikó, Herman, Bianka Edina, Jójárt, Rebeka, Herman, Kevin Stefán, Wölfling, János, Schneider, Gyula, Varga, Mónika, Tömböly, Csaba, Rižner, Tea Lanišnik, Szécsi, Mihály, Mernyák, Erzsébet
Format Journal Article
LanguageEnglish
Published ABINGDON Taylor & Francis 01.01.2018
Taylor & Francis Group
Subjects
17β-HSD1
aromatase
Biochemistry & Molecular Biology
Chemistry, Medicinal
Estrone
halogenations
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Research Paper
Science & Technology
STS
DESIGN
17-BETA-HYDROXYSTEROID DEHYDROGENASE
aromatase
SPECIFICITY
ANALOGS
STEROID SULFATASE INHIBITORS
BREAST-CANCER
IN-VITRO
STS
PLACENTAL AROMATASE CYTOCHROME-P-450
17 beta-HSD1
halogenations
ESTRADIOL
Estrone
BINDING
17β-HSD1
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Summary: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.
Bibliography:These authors contributed equally to this work.
Supplemental data for this article can be accessed here.
ISSN:1475-6366
1475-6374
DOI:10.1080/14756366.2018.1490731