- Macrodiolide Diversification Reveals Broad Immunosuppressive Activity That Impairs the cGAS-STING Pathway
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The development of new immunomodulatory agents can impact various areas of medicine. In particular, compounds with the ability to modulate innate immunological pathways hold significant unexplored potential. Herein, we report a modular synthetic approach to the macrodiolide natural product (?)-vermiculine, an agent previously shown to possess diverse biological effects, including cytotoxic and immunosuppressive activity. The synthesis allows for a high degree of flexibility in modifying the macrocyclic framework, including the formation of all possible stereoisomers. In total, 18 analogues were prepared. Two analogues with minor structural modifications showed clearly enhanced cancer cell line selectivity and reduced toxicity. Moreover, these compounds possessed broad inhibitory activity against innate immunological pathways in human PBMCs, including the DNA-sensing cGAS-STING pathway. Initial mechanistic characterization suggests a surprising impairment of the STING-TBK1 interaction.
- Biltoft, Mette,Jakobsen, Martin R.,Jennet, Kira M.,Kristensen, Tobias F.,Liu, Han,Ottosen, Rasmus N.,Poulsen, Thomas B.,Svenningsen, Esben B.
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supporting information
p. 18734 - 18741
(2021/07/19)
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- Vermiculin derivatives. Part 1: Synthesis of vermiculin derivatives
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Hydrogenation of the macrodiolide antibiotic vermiculin (1) over Adams catalyst afforded [8S,16S]-8,16-bis (2'-oxopropyl)-1,9-dioxacyclohexadeca-2,5,10,13-tetrone (2). [8S,16S]-8,16-bis (2'-oxopropyl)-13-hydroxy-1,9-dioxacyclohexadeca-2,5,10-trione (3), [8S,16S]-8,16-bis(2'oxopropyl)-1,9-dioxacyclohexadeca-2,5,10-trione (4) together with [7S]-4,9-dioxo-7-(4',9'-dioxodecanoyloxy)decanoic acid (5). Hydrogenation of diolide 1 over Pd-C gave tetrahydrovermiculin (2) only. The prepared compounds showed lower antibacterial and cytotoxic activities than vermiculin (1).
- Proksa,Uhrin,Adamcova,Muckova,Fuska
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p. 738 - 740
(2007/10/02)
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