Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors
| Autor: | Daniele Passarella, Federica Catti, Irene Basili, Paola Infante, Elisa Bonandi, Bruno Botta, Mattia Mori, Andrea Calcaterra, Lucia Di Marcotullio |
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| Rok vydání: | 2021 |
| Předmět: |
withaferin A
natural products In silico 2-piperidine ethanol Hedgehog inhibitors Hedgehog signalling pathway Hedgehog Proteins Signal Transduction Antineoplastic Agents Withanolides Computational biology 010402 general chemistry 01 natural sciences Catalysis chemistry.chemical_compound Biological property Hh signalling pathway Hedgehog Functional evaluation Full Paper 010405 organic chemistry Organic Chemistry General Chemistry Full Papers Hedgehog signaling pathway 0104 chemical sciences chemistry Withaferin A |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) |
| ISSN: | 1521-3765 |
| Popis: | Withanolides constitute a well‐known family of plant‐based alkaloids characterised by widespread biological properties, including the ability of interfering with Hedgehog (Hh) signalling pathway. Following our interest in natural products and in anticancer compounds, we report here the synthesis of a new class of Hh signalling pathway inhibitors, inspired by withaferin A, the first isolated member of withanolides. The decoration of our scaffolds was rationally supported by in silico studies, while functional evaluation revealed promising candidates, confirming once again the importance of natural products as inspiration source for the discovery of novel bioactive compounds. A stereoselective approach, based on Brown chemistry, allowed the obtainment and the functional evaluation of the enantiopure hit compounds. The structural and functional properties of withaferin A suggested the design of a new candidate for Hedgehog pathway inhibitions. The enantioselective synthesis permitted the identification of two promising hits. |
| Databáze: | OpenAIRE |
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