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Design and Synthesis of New Withaferin A Inspired Hedgehog Pathway Inhibitors
Author(s) -
Bonandi Elisa,
Mori Mattia,
Infante Paola,
Basili Irene,
Di Marcotullio Lucia,
Calcaterra Andrea,
Catti Federica,
Botta Bruno,
Passarella Daniele
Publication year - 2021
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.202100315
Subject(s) - withaferin a , enantiopure drug , in silico , hedgehog signaling pathway , hedgehog , computational biology , chemistry , signalling pathways , stereochemistry , biology , biochemistry , signal transduction , withania somnifera , gene , enantioselective synthesis , medicine , alternative medicine , pathology , catalysis
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.