Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1).

2.50
Hdl Handle:
http://hdl.handle.net/10033/249356
Title:
Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1).
Authors:
Spadaro, Alessandro; Negri, Matthias; Marchais-Oberwinkler, Sandrine; Bey, Emmanuel; Frotscher, Martin
Abstract:
17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC₅₀-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics.
Affiliation:
Pharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.
Citation:
Hydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 2012, 7 (1):e29252 PLoS ONE
Journal:
PloS one
Issue Date:
2012
URI:
http://hdl.handle.net/10033/249356
DOI:
10.1371/journal.pone.0029252
PubMed ID:
22242164
Type:
Article
Language:
en
ISSN:
1932-6203
Appears in Collections:
Publications of the divsion Wirkstoffdesign und Optimierung (DDOP)

Full metadata record

DC FieldValue Language
dc.contributor.authorSpadaro, Alessandroen_GB
dc.contributor.authorNegri, Matthiasen_GB
dc.contributor.authorMarchais-Oberwinkler, Sandrineen_GB
dc.contributor.authorBey, Emmanuelen_GB
dc.contributor.authorFrotscher, Martinen_GB
dc.date.accessioned2012-10-18T11:35:47Z-
dc.date.available2012-10-18T11:35:47Z-
dc.date.issued2012-
dc.identifier.citationHydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 2012, 7 (1):e29252 PLoS ONEen_GB
dc.identifier.issn1932-6203-
dc.identifier.pmid22242164-
dc.identifier.doi10.1371/journal.pone.0029252-
dc.identifier.urihttp://hdl.handle.net/10033/249356-
dc.description.abstract17β-estradiol (E2), the most potent estrogen in humans, known to be involved in the development and progession of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-HSD1, which catalyses the reduction of the weak estrogen estrone (E1) to E2, is often overexpressed in breast cancer and endometriotic tissues. An inhibition of 17β-HSD1 could selectively reduce the local E2-level thus allowing for a novel, targeted approach in the treatment of EDD. Continuing our search for new nonsteroidal 17β-HSD1 inhibitors, a novel pharmacophore model was derived from crystallographic data and used for the virtual screening of a small library of compounds. Subsequent experimental verification of the virtual hits led to the identification of the moderately active compound 5. Rigidification and further structure modifications resulted in the discovery of a novel class of 17β-HSD1 inhibitors bearing a benzothiazole-scaffold linked to a phenyl ring via keto- or amide-bridge. Their putative binding modes were investigated by correlating their biological data with features of the pharmacophore model. The most active keto-derivative 6 shows IC₅₀-values in the nanomolar range for the transformation of E1 to E2 by 17β-HSD1, reasonable selectivity against 17β-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17β-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17β-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17β-HSD1 inhibitors for the development of potential therapeutics.en_GB
dc.language.isoenen
dc.rightsArchived with thanks to PloS oneen_GB
dc.subject.mesh17-Hydroxysteroid Dehydrogenasesen_GB
dc.subject.meshCell Line, Tumoren_GB
dc.subject.meshCrystallizationen_GB
dc.subject.meshEnzyme Inhibitorsen_GB
dc.subject.meshEstrogen Receptor alphaen_GB
dc.subject.meshEstrogen Receptor betaen_GB
dc.subject.meshEstrogens, Non-Steroidalen_GB
dc.subject.meshHumansen_GB
dc.subject.meshLigandsen_GB
dc.subject.meshModels, Molecularen_GB
dc.subject.meshStructure-Activity Relationshipen_GB
dc.subject.meshThiazolesen_GB
dc.titleHydroxybenzothiazoles as new nonsteroidal inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1).en
dc.typeArticleen
dc.contributor.departmentPharmaceutical and Medicinal Chemistry, Saarland University, Saarbrücken, Germany.en_GB
dc.identifier.journalPloS oneen_GB

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