Synthesis of Indofulvin Pseudo-Natural Products Yields a New Autophagy Inhibitor Chemotype.
autophagy
cell painting
oxa-Pictet-Spengler reaction
pseudo-natural products
Journal
Advanced science (Weinheim, Baden-Wurttemberg, Germany)
ISSN: 2198-3844
Titre abrégé: Adv Sci (Weinh)
Pays: Germany
ID NLM: 101664569
Informations de publication
Date de publication:
10 2021
10 2021
Historique:
revised:
14
07
2021
received:
17
05
2021
pubmed:
5
8
2021
medline:
12
2
2022
entrez:
4
8
2021
Statut:
ppublish
Résumé
Chemical and biological limitations in bioactive compound design based on natural product (NP) structure can be overcome by the combination of NP-derived fragments in unprecedented arrangements to afford "pseudo-natural products" (pseudo-NPs). A new pseudo-NP design principle is described, i.e., the combination of NP-fragments by transformations that are not part of current biosynthesis pathways. A collection of indofulvin pseudo-NPs is obtained from 2-hydroxyethyl-indoles and ketones derived from the fragment-sized NP griseofulvin by means of an iso-oxa-Pictet-Spengler reaction. Cheminformatic analysis indicates that the indofulvins reside in an area of chemical space sparsely covered by NPs, drugs, and drug-like compounds and they may combine favorable properties of these compound classes. Biological evaluation of the compound collection in different cell-based assays and the unbiased high content cell painting assay reveal that the indofulvins define a new autophagy inhibitor chemotype that targets mitochondrial respiration.
Identifiants
pubmed: 34346568
doi: 10.1002/advs.202102042
pmc: PMC8498912
doi:
Substances chimiques
Biological Products
0
Indoles
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e2102042Subventions
Organisme : Alexander von Humboldt-Stiftung
Informations de copyright
© 2021 The Authors. Advanced Science published by Wiley-VCH GmbH.
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