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

ABSTRACT: 17?-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. 17?-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 17?-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 17?-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 17?-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 IC??-values in the nanomolar range for the transformation of E1 to E2 by 17?-HSD1, reasonable selectivity against 17?-HSD2 but pronounced affinity to the estrogen receptors (ERs). On the other hand, the best amide-derivative 21 shows only medium 17?-HSD1 inhibitory activity at the target enzyme as well as fair selectivity against 17?-HSD2 and ERs. The compounds 6 and 21 can be regarded as first benzothiazole-type 17?-HSD1 inhibitors for the development of potential therapeutics.

SUBMITTER: Spadaro A

PROVIDER: S-EPMC3252304 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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

Spadaro Alessandro A Negri Matthias M Marchais-Oberwinkler Sandrine S Bey Emmanuel E Frotscher Martin M

PloS one 20120105 1

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 ...[more]

PMID: 22242164

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Project description:17?-Hydroxysteroid dehydrogenase type 1 (17?-HSD1) catalyzes the reduction of estrone to estradiol, which is the most potent estrogen in humans. Inhibition of 17?-HSD1 and thereby reducing the intracellular estradiol concentration is thus a promising approach for the treatment of estrogen dependent diseases. In the past, several steroidal and non-steroidal inhibitors of 17?-HSD1 have been described but so far there is no cocrystal structure of the latter in complex with 17?-HSD1. However, a distinct knowledge of active site topologies and protein-ligand interactions is a prerequisite for structure-based drug design and optimization. An elegant strategy to enhance this knowledge is to compare inhibition values obtained for one compound toward ortholog proteins from various species, which are highly conserved in sequence and differ only in few residues. In this study the inhibitory potencies of selected members of different non-steroidal inhibitor classes toward marmoset 17?-HSD1 were determined and the data were compared with the values obtained for the human enzyme. A species specific inhibition profile was observed in the class of the (hydroxyphenyl)naphthols. Using a combination of computational methods, including homology modelling, molecular docking, MD simulation, and binding energy calculation, a reasonable model of the three-dimensional structure of marmoset 17?-HSD1 was developed and inhibition data were rationalized on the structural basis. In marmoset 17?-HSD1, residues 190 to 196 form a small ?-helix, which induces conformational changes compared to the human enzyme. The docking poses suggest these conformational changes as determinants for species specificity and energy decomposition analysis highlighted the outstanding role of Asn152 as interaction partner for inhibitor binding. In summary, this strategy of comparing the biological activities of inhibitors toward highly conserved ortholog proteins might be an alternative to laborious x-ray or site-directed mutagenesis experiments in certain cases. Additionally, it facilitates inhibitor design and optimization by offering new information on protein-ligand interactions.

Dataset Information

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

Publications

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

Similar Datasets

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