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Synthesis of 20‐Membered Macrocyclic Pseudo‐Natural Products Yields Inducers of LC3 Lipidation

Year: 2022
Type: article
Abstract: Design and synthesis of pseudo-natural products (PNPs) through recombination of natural product (NP) fragments in unprecedented arrangements enables the discovery of novel biologically relevant chemical matter. With a view to wider coverage of NP-inspired chemical and biological space, we describe the combination of this principle with macrocycle formation. PNP-macrocycles were synthesized efficiently in a stereoselective one-pot procedure including the 1,3-dipolar cycloadditions of different dipolarophiles with dimeric cinchona alkaloid-derived azomethine ylides formed in situ. The 20-membered bis-cycloadducts embody 18 stereocenters and an additional fragment-sized NP-structure. After further functionalization, a collection of 163 macrocyclic PNPs was obtained. Biological investigation revealed potent inducers of the lipidation of the microtubule associated protein 1 light chain 3 (LC3) protein, which plays a prominent role in various autophagy-related processes.
DOI: 10.1002/anie.202114328
Authors: Georg Niggemeyer, Anastasia Knyazeva, Raphael Gasper, Dale Corkery, Pia Bodenbinder, Julian J. Holstein, Sonja Sievers, Yao‐Wen Wu, Herbert Waldmann
Language: English
Field: Chemistry
Open Access status: hybrid
Estimated APC paid: $5,100
Funders: Göran Gustafssons Stiftelser, Göran Gustafssons Stiftelse för Naturvetenskaplig och Medicinsk Forskning, Knut och Alice Wallenbergs Stiftelse, Max-Planck-Gesellschaft, Paul Scherrer Institut, Vetenskapsrådet, Umeå Universitet, European Research Council
OpenAlex ID: W4206113121
FWCI: 1.663
Cites: 52
Cited by: 20
Related to: 10