Exploring the Potential of Anthraquinone-Based Hybrids for Identifying a Novel Generation of Antagonists for the Smoothened Receptor in HH-Dependent Tumour.
Hedgehog pathway
SMO antagonists
anthraquinones
hybrid compounds
natural products
Journal
Chemistry (Weinheim an der Bergstrasse, Germany)
ISSN: 1521-3765
Titre abrégé: Chemistry
Pays: Germany
ID NLM: 9513783
Informations de publication
Date de publication:
08 Nov 2023
08 Nov 2023
Historique:
received:
13
07
2023
medline:
10
11
2023
pubmed:
11
8
2023
entrez:
11
8
2023
Statut:
ppublish
Résumé
Natural products (NPs) are highly profitable pharmacological tools due to their chemical diversity and ability to modulate biological systems. Accessing new chemical entities while retaining the biological relevance of natural chemotypes is a fundamental goal in the design of novel bioactive compounds. Notably, NPs have played a crucial role in understanding Hedgehog (HH) signalling and its pharmacological modulation in anticancer therapy. However, HH antagonists developed so far have shown several limitations, thus growing interest in the design of second-generation HH inhibitors. Through smart manipulation of the NPs core-scaffold, unprecedented and intriguing architectures have been achieved following different design strategies. This study reports the rational design and synthesis of a first and second generation of anthraquinone-based hybrids by combining the rhein scaffold with variously substituted piperazine nuclei that are structurally similar to the active portion of known SMO antagonists, the main transducer of the HH pathway. A thorough functional and biological investigation identified RH2_2 and RH2_6 rhein-based hybrids as valuable candidates for HH inhibition through SMO antagonism, with the consequent suppression of HH-dependent tumour growth. These findings also corroborated the successful application of the NPs-based hybrid design strategy in the development of novel NP-based SMO antagonists.
Identifiants
pubmed: 37565343
doi: 10.1002/chem.202302237
doi:
Substances chimiques
Smoothened Receptor
0
rhein
YM64C2P6UX
Hedgehog Proteins
0
Antineoplastic Agents
0
Anthraquinones
0
9,10-anthraquinone
030MS0JBDO
Receptors, G-Protein-Coupled
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e202302237Subventions
Organisme : Ministero dell'Istruzione, dell'Università e della Ricerca
ID : PRIN 2017BF3PXZ003
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : #IG20801
Organisme : Associazione Italiana per la Ricerca sul Cancro
ID : MFAG 2021-ID. 26536
Informations de copyright
© 2023 The Authors. Chemistry - A European Journal published by Wiley-VCH GmbH.
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