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

Georg Niggemeyer, Anastasia Knyazeva, Raphael Gasper, Dale Corkery, Pia Bodenbinder, Julian J Holstein, Sonja Sievers, Yao-Wen Wu, Herbert Waldmann

Angewandte Chemie (International ed. in English) 2022 Mar 07

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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. © 2022 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.

Citation

Georg Niggemeyer, Anastasia Knyazeva, Raphael Gasper, Dale Corkery, Pia Bodenbinder, Julian J Holstein, Sonja Sievers, Yao-Wen Wu, Herbert Waldmann. Synthesis of 20-Membered Macrocyclic Pseudo-Natural Products Yields Inducers of LC3 Lipidation. Angewandte Chemie (International ed. in English). 2022 Mar 07;61(11):e202114328