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11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches

Rollinger, Judith M. and Kratschmar, Denise V. and Schuster, Daniela and Pfisterer, Petra H. and Gumy, Christel and Aubry, Evelyne M. and Brandstötter, Sarah and Stuppner, Hermann and Wolber, Gerhard and Odermatt, Alex. (2010) 11beta-Hydroxysteroid dehydrogenase 1 inhibiting constituents from Eriobotrya japonica revealed by bioactivity-guided isolation and computational approaches. Bioorganic & medicinal chemistry, Vol. 18, H. 4. pp. 1507-1515.

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Official URL: http://edoc.unibas.ch/dok/A5841137

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Abstract

The inhibition of 11beta-hydroxysteroid dehydrogenase 1 (11beta-HSD1), which catalyzes the conversion of inactive 11-ketoglucocorticoids to active 11beta-hydroxyglucocorticoids, emerged as promising strategy to treat symptoms of the metabolic syndrome, including obesity and type 2 diabetes. In this study the leaves of the anti-diabetic medicinal plant loquat (Eriobotrya japonica) were phytochemically investigated following hints from a pharmacophore-based virtual screening and a bioactivity-guided approach. Determination of the 11beta-HSD1 and 11beta-HSD2 inhibitory activities in cell lysates revealed triterpenes from the ursane type as selective, low micro-molar inhibitors of 11beta-HSD1, that is, corosolic acid (1), 3-epicorosolic acid methyl ester (4), 2-alpha hydroxy-3-oxo urs-12-en-28-oic acid (6), tormentic acid methyl ester (8), and ursolic acid (9). Importantly, a mixture of loquat constituents with moderate activities displayed a pronounced additive effect. By means of molecular modeling studies and the identification of the 11beta-HSD1-inhibiting 11-keto-ursolic acid (17) and 3-acetyl-11-keto-ursolic acid (18) a structure-activity relationship was deduced for this group of pentacyclic triterpenes. The mechanism of action elucidated in the present work together with the previously determined pharmacological activities provides these natural products with an astonishing multi-targeted anti-diabetic profile.
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Pharmazie > Molecular and Systems Toxicology (Odermatt)
UniBasel Contributors:Odermatt, Alex and Kratschmar, Denise
Item Type:Article, refereed
Article Subtype:Research Article
Bibsysno:Link to catalogue
Publisher:Pergamon
ISSN:0968-0896
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:14 Sep 2012 07:17
Deposited On:14 Sep 2012 06:37

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