Biology-Oriented Synthesis of a Withanolide-Inspired Compound Collection Reveals Novel Modulators of Hedgehog Signaling

Biology‐oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans‐hydrindane dehydro‐δ‐lactone motif defines the characteristic scaffold of the steroid‐like withanolides, a plant‐derived...

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Published inAngewandte Chemie Vol. 127; no. 19; pp. 5688 - 5694
Main Authors Švenda, Jakub, Sheremet, Michael, Kremer, Lea, Maier, Lukáš, Bauer, Jonathan O., Strohmann, Carsten, Ziegler, Slava, Kumar, Kamal, Waldmann, Herbert
Format Journal Article
LanguageEnglish
German
Published Weinheim WILEY-VCH Verlag 04.05.2015
WILEY‐VCH Verlag
Wiley Subscription Services, Inc
Subjects
Biochemistry
Biological
Biological activity
Biologie-orientierte Synthese
Chemische Biologie
Chemistry
Collection
Functional groups
Hedgehog-Signalweg
Inhibitors
Modulators
Natural products
Naturstoffe
Proteins
Synthesis
Totalsynthese
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Summary:Biology‐oriented synthesis employs the structural information encoded in complex natural products to guide the synthesis of compound collections enriched in bioactivity. The trans‐hydrindane dehydro‐δ‐lactone motif defines the characteristic scaffold of the steroid‐like withanolides, a plant‐derived natural product class with a diverse pattern of bioactivity. A withanolide‐inspired compound collection was synthesized by making use of three key intermediates that contain this characteristic framework derivatized with different reactive functional groups. Biological evaluation of the compound collection in cell‐based assays that monitored biological signal‐transduction processes revealed a novel class of Hedgehog signaling inhibitors that target the protein Smoothened. BIOS führt mittels stereoselektiver Synthese zu einer Substanzbibliothek mit einem trans‐Hydrindandehydro‐δ‐lacton‐Gerüst, die auf den Withanolid‐Naturstoffen basiert. Biologische Studien dieser Derivate führten zur Identifizierung neuer leistungsfähiger Inhibitoren des Hedgehog‐Signalwegs, die an das Protein Smoothened binden.
Bibliography:European Regional Development Fund - No. CZ.1.05/1.1.00/02.0123
Alexander von Humboldt Foundation
European Social Fund
istex:30C8B1083101BFC0FAE2E55D2E4DAA460929538A
Fonds der Chemischen Industrie
ArticleID:ANGE201500112
This research was supported by the European Research Council under the European Union's Seventh Framework Programme (FP7/2007-2013; ERC Grant 268309 to H.W.) and the Max Planck Society. J.S. and M.S. thank the Alexander von Humboldt Foundation and the Fonds der Chemischen Industrie for a post-doctoral and a Kekulé fellowship, respectively. L.M. thanks the European Regional Development Fund-Project FNUSA-ICRC (CZ.1.05/1.1.00/02.0123), the European Social Fund, and the State Budget of the Czech Republic.
Max Planck Society
European Union - No. 268309
State Budget of the Czech Republic
ark:/67375/WNG-4GQDH57F-J
These authors contributed equally to this work.
This research was supported by the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007‐2013; ERC Grant 268309 to H.W.) and the Max Planck Society. J.S. and M.S. thank the Alexander von Humboldt Foundation and the Fonds der Chemischen Industrie for a post‐doctoral and a Kekulé fellowship, respectively. L.M. thanks the European Regional Development Fund—Project FNUSA–ICRC (CZ.1.05/1.1.00/02.0123), the European Social Fund, and the State Budget of the Czech Republic.
ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.201500112