Total Synthesis and Functional Evaluation of IORs, Sulfonolipid‐based Inhibitors of Cell Differentiation in Salpingoeca rosetta

The choanoflagellate Salpingoeca rosetta is an important model system to study the evolution of multicellularity. In this study we developed a new, modular, and scalable synthesis of sulfonolipid IOR‐1A (six steps, 27 % overall yield), which acts as bacterial inhibitor of rosette formation in S. ros...

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Published in:Angewandte Chemie 2022-10, Vol.134 (41), p.n/a
Main Authors: Raguž, Luka, Peng, Chia‐Chi, Rutaganira, Florentine U. N., Krüger, Thomas, Stanišić, Aleksa, Jautzus, Theresa, Kries, Hajo, Kniemeyer, Olaf, Brakhage, Axel A., King, Nicole, Beemelmanns, Christine
Format: Article
Language:English
Subjects:
Cell differentiation
Chemical Probes
Chemistry
Cross coupling
Differentiation (biology)
Fluorescence
Localization
Microbial Natural Products
Proteomic Profiling
Proteomics
Reagents
Rosette formation
Salpingoeca rosetta
Sphingolipids
Sulfonic acid
Tartaric acid
Total Synthesis
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Summary:The choanoflagellate Salpingoeca rosetta is an important model system to study the evolution of multicellularity. In this study we developed a new, modular, and scalable synthesis of sulfonolipid IOR‐1A (six steps, 27 % overall yield), which acts as bacterial inhibitor of rosette formation in S. rosetta. The synthesis features a decarboxylative cross‐coupling reaction of a sulfonic acid‐containing tartaric acid derivative with alkyl zinc reagents. Synthesis of 15 modified IOR‐1A derivatives, including fluorescent and photoaffinity‐based probes, allowed quantification of IOR‐1A, localization studies within S. rosetta cells, and evaluation of structure‐activity relations. In a proof of concept study, an inhibitory bifunctional probe was employed in proteomic profiling studies, which allowed to deduce binding partners in bacteria and S. rosetta. These results showcase the power of synthetic chemistry to decipher the biochemical basis of cell differentiation processes within S. rosetta. A new and modular synthesis of the rosette‐inhibitor sulfonolipid IOR‐1A and chemical probes was achieved via decarboxylative cross‐coupling reaction of a desymmetrized tartaric acid derivatives and alkyl zinc reagents of choice. Synthesized congeners and bifunctional probes allowed to determine structure‐activity relation to profile binding partners in producer and recipient for the first time.
ISSN:0044-8249
1521-3757
DOI:10.1002/ange.202209105