Comparative investigation of the<i>in vitro</i>inhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17<b>β</b>-hydroxysteroid dehydrogenase type 1

Herman, Bianka Edina; Szabó, Johanna; Bacsa, Ildikó; Wölfling, János; Schneider, Gyula; Bálint, Mónika; Hetényi, Csaba; Mernyák, Erzsébet; Szécsi, Mihály

doi:10.1080/14756366.2016.1204610

Cited by 13 publications

(24 citation statements)

References 52 publications

(84 reference statements)

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“…The direction of the reaction depends on the substrate ( Hanukoglu, 1992 ; Thomas and Potter, 2013 ). 17β-HSD1 predominantly catalyzes the NADPH-promoted stereospecific reduction of estrone to the more active estradiol ( Thomas and Potter, 2013 ; Herman et al, 2016 ). 17β-HSD2 shows oxidative activity and is capable of catalyzing the conversion of estradiol, testosterone, and dihydrotestosterone to their less-active 17-keto forms, estrone, A-dione, and 5α-androstanedione, respectively ( Rantakari et al, 2008 ).…”

Section: Steroid Hormonesmentioning

confidence: 99%

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

2018

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The steroid hormones progestagens, estrogens, androgens, and glucocorticoids as well as their precursor cholesterol are required for successful establishment and maintenance of pregnancy and proper development of the fetus. The human placenta forms at the interface of maternal and fetal circulation. It participates in biosynthesis and metabolism of steroids as well as their regulated exchange between maternal and fetal compartment. This review outlines the mechanisms of human placental handling of steroid compounds. Cholesterol is transported from mother to offspring involving lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SRB1) as well as ATP-binding cassette (ABC)-transporters, ABCA1 and ABCG1. Additionally, cholesterol is also a precursor for placental progesterone and estrogen synthesis. Hormone synthesis is predominantly performed by members of the cytochrome P-450 (CYP) enzyme family including CYP11A1 or CYP19A1 and hydroxysteroid dehydrogenases (HSDs) such as 3β-HSD and 17β-HSD. Placental estrogen synthesis requires delivery of sulfate-conjugated precursor molecules from fetal and maternal serum. Placental uptake of these precursors is mediated by members of the solute carrier (SLC) family including sodium-dependent organic anion transporter (SOAT), organic anion transporter 4 (OAT4), and organic anion transporting polypeptide 2B1 (OATP2B1). Maternal–fetal glucocorticoid transport has to be tightly regulated in order to ensure healthy fetal growth and development. For that purpose, the placenta expresses the enzymes 11β-HSD 1 and 2 as well as the transporter ABCB1. This article also summarizes the impact of diverse compounds and diseases on the expression level and activity of the involved transporters, receptors, and metabolizing enzymes and concludes that the regulatory mechanisms changing the physiological to a pathophysiological state are barely explored. The structure and the cellular composition of the human placental barrier are introduced. While steroid production, metabolism and transport in the placental syncytiotrophoblast have been explored for decades, few information is available for the role of placental-fetal endothelial cells in these processes. With regard to placental structure and function, significant differences exist between species. To further decipher physiologic pathways and their pathologic alterations in placental steroid handling, proper model systems are mandatory.

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Section: Steroid Hormonesmentioning

confidence: 99%

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

2018

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“…Certain other chemical modifications of the estrane skeleton, such as the inversion of the configuration at C-13 or the opening of ring D, may result in the complete loss of hormonal activity 12–15 . We have promising preliminary results concerning the design, synthesis and biochemical evaluation of 17β-HSD1 inhibitors based on hormonally inactive 13α-estrane core 16 . 13α-Estrone ( 9 , Scheme 2 ) itself was proved to be a potent inhibitor with an IC 50 comparable to that of the natural substrate E1.…”

Section: Introductionmentioning

confidence: 99%

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

Bacsa

Herman

Jójárt

et al. 2018

Journal of Enzyme Inhibition and Medicinal Chemistry

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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.

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“…All the halogenated 3-hydroxy and the 4-substituted regioisomers of 3-methyl ethers displayed substantial inhibitory activity against the 17β-hydroxysteroid dehydrogenase type 1 enzyme (17β-HSD1). Certain derivatives displayed a similar or more pronounced effect than those of their parent compounds 13α-estrone or 13α-estrone 3-methyl ether [13]. The 17β-HSD1 enzyme is responsible for the stereospecific reduction of prehormone estrone into the main estrogenic hormone 17β-estradiol [14–15].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

Bacsa¹,

Jójárt²,

Wölfling³

et al. 2017

Beilstein J. Org. Chem.

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Novel 13α-estrone derivatives were synthesized by Sonogashira coupling. Transformations of 2- or 4-iodo regioisomers of 13α-estrone and its 3-methyl ether were carried out under different conditions in a microwave reactor. The 2-iodo isomers were reacted with para-substituted phenylacetylenes using Pd(PPh3)4 as catalyst and CuI as a cocatalyst. Coupling reactions of 4-iodo derivatives could be achieved by changing the catalyst to Pd(PPh3)2Cl2. The product phenethynyl derivatives were partially or fully saturated. Compounds bearing a phenolic OH group furnished benzofurans under the conditions used for the partial saturation. The inhibitory effects of the compounds on human placental 17β-hydroxysteroid dehydrogenase type 1 isozyme (17β-HSD1) were investigated by an in vitro radiosubstrate incubation method. Certain 3-hydroxy-2-phenethynyl or -phenethyl derivatives proved to be potent 17β-HSD1 inhibitors, displaying submicromolar IC50 values.

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Comparative investigation of thein vitroinhibitory potencies of 13-epimeric estrones and D-secoestrones towards 17β-hydroxysteroid dehydrogenase type 1

Cited by 13 publications

References 52 publications

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta

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

Synthesis of novel 13α-estrone derivatives by Sonogashira coupling as potential 17β-HSD1 inhibitors

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