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Concise Total Syntheses of (+)-Brefeldin A, Diastereomers and Analogs and Their Biological Activity
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SYSNO ASEP 0576142 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Ostatní články Title Concise Total Syntheses of (+)-Brefeldin A, Diastereomers and Analogs and Their Biological Activity Author(s) Klychnikov, Mikhail (UOCHB-X) ORCID
Pohl, Radek (UOCHB-X) RID, ORCID
Císařová, I. (CZ)
Hájek, Miroslav (UOCHB-X) RID, ORCID
Jahn, Ullrich (UOCHB-X) ORCIDArticle number e202300030 Source Title ChemistryEurope. - : Wiley - ISSN 2751-4765
Roč. 1, č. 2 (2023)Number of pages 11 s. Language eng - English Country DE - Germany Keywords brefeldin A ; Golgi apparatus ; macrolactones ; natural products ; total synthesis OECD category Organic chemistry R&D Projects GA16-18513S GA ČR - Czech Science Foundation (CSF) Method of publishing Open access Institutional support UOCHB-X - RVO:61388963 DOI https://doi.org/10.1002/ceur.202300030 Annotation Brefeldin A is an important natural product and biochemical tool with cell-modulating and other diverse biological activities. To explore its chemical space, a generally applicable strategy for total syntheses of naturally occurring (+)-brefeldin A (BFA), 2-epi-BFA, their diastereomers and analogs with varying macrocyclic ring size is reported. The five-membered ring fragment was constructed by a short three-step sequence consisting of tandem nucleophilic epoxide opening/Brook rearrangement/radical oxygenation and subsequent thermal radical cyclization based on the persistent radical effect. Further key steps are asymmetric aldehyde vinylation, which enables control of the absolute configuration at the allylic hydroxy group of BFA, cross-metatheses reactions for attachment of the northern and southern side chains to the cyclopentane unit and final Shiina macrolactonization. The cytotoxic activity of all compounds was determined, and several analogs proved to be similarly active as BFA, providing insight about regions of the skeleton that can be varied or have to be conserved with respect to their biological activities. Fluorescence microscopy revealed that BFA and some non-natural analogs disassemble the Golgi apparatus in cells with large variation of the disassembly and subsequent reassembly times. Workplace Institute of Organic Chemistry and Biochemistry Contact asep@uochb.cas.cz ; Kateřina Šperková, Tel.: 232 002 584 ; Jana Procházková, Tel.: 220 183 418 Year of Publishing 2024 Electronic address https://doi.org/10.1002/ceur.202300030
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