Total Synthesis of Tagitinins, Goyazensolide and Related Furanoheliangolides and their Covalent Interaction with Importin‐5 (IPO5)

Article Article scientifique Article Total Synthesis of Tagitinins, Goyazensolide and Related Furanoheliangolides and their Covalent Interaction with Importin‐5 (IPO5) eng 2024-11-08 2024-11 author Liu Weilong Department, of Organic Chemistry Faculty of Science University of Geneva 1205 Geneva Switzerland 882504 author Patouret Rémi Department, of Organic Chemistry Faculty of Science University of Geneva 1205 Geneva Switzerland 859595 author Peev Elsa Department, of Organic Chemistry Faculty of Science University of Geneva 1205 Geneva Switzerland 853001 author Barluenga Badiola Sofia Department, of Organic Chemistry Faculty of Science University of Geneva 1205 Geneva Switzerland 810177 Département de chimie organique (CHIOR) author Winssinger Nicolas 0000-0003-1636-7766 Department, of Organic Chemistry Faculty of Science University of Geneva 1205 Geneva Switzerland 769664 Département de chimie organique (CHIOR) e202400122 10.1002/hlca.202400122 0018-019X https://onlinelibrary.wiley.com/doi/10.1002/hlca.202400122 Herein, we detail an extension of our research on the synthesis of a small library of furanoheliangolides and the characterization of the covalent interaction between goyazensolide and IPO5. Using a build‐couple‐pair strategy, we assembled a small library of germacrene‐type lactones and diversified them into eight groups of structurally different analogues. The germacrene lactones were synthesized using Sonogashira coupling and Barbier‐type macrocyclization, while the furanoheliangolides were further elaborated through gold‐catalyzed transannulation followed by esterification. This synthetic approach enabled the generation of a goyazensolide alkyne‐tagged cellular probe, which was used to identify the selective binding between goyazensolide and the oncoprotein importin‐5 (IPO5). Mass spectrometry analysis of the proteolytic digest from the reaction between the goyazensolide probe and a recombinant IPO5 indicated a covalent engagement at Cys560 of IPO5, which was confirmed by site‐directed mutagenesis. Dewey 540 Swiss National Science Foundation Chemical biology probes from natural product synthesis, artificial biochemical circuitry and antagomirs 188406 CH Projects Swiss National Science Foundation NCCR Chemical Biology - Visualisation and Control of Biological Processes Using Chemistry (phase III) 185898 CH Programmes 36 Département de chimie organique 141 false 762 Groupe Winssinger Helvetica chimica acta 107 11 20b3b9a7-ef5e-4d9a-a251-3debeeb86fb1 Article (Published version) Public Helvetica_Chimica_Acta_-_2024_-_Liu.pdf 14927264 application/pdf CC BY-NC-4.0 12983c0167c588218f76bb156bbbab0ca677611f6d4309cc202b3b87ad0c1d23 openAccess Faculté des sciences / Section de chimie et biochimie / Département de chimie organique

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Total Synthesis of Tagitinins, Goyazensolide and Related Furanoheliangolides and their Covalent Interaction with Importin‐5 (IPO5)	Helvetica chimica acta			2024	48	37

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