RESUMEN
A Natural Compound Library containing myxobacterial secondary metabolites was screened in murine macrophages for novel activators of IL-1ß maturation and secretion. The most potent of three hits in total was a so far undescribed metabolite, which was identified from the myxobacterium Hyalangium minutum strain Hym3. While the planar structure of 1 was elucidated by high resolution mass spectrometry and NMR data yielding an asymmetric boron containing a macrodiolide core structure, its relative stereochemistry of all 20 stereocenters of the 42-membered ring was assigned by rotating frame Overhause effect spectroscopy correlations, 1H,1H, and 1H,13C coupling constants, and by comparison of 13C chemical shifts to those of the structurally related metabolites tartrolon B-D. The absolute stereochemistry was subsequently assigned by Mosher's and Marfey's methods. Further functional studies revealed that hyaboron and other boronated natural compounds resulted in NLRP3 inflammasome dependent IL-1ß maturation, which is most likely due to their ability to act as potassium ionophores. Moreover, besides its inflammasome-stimulatory activity in human and mouse cells, hyaboron (1) showed additional diverse biological activities, including antibacterial and antiparasitic effects.
Asunto(s)
Adyuvantes Inmunológicos/farmacología , Compuestos de Boro/farmacología , Macrólidos/farmacología , Myxococcales/química , Adyuvantes Inmunológicos/química , Animales , Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Antineoplásicos/química , Antineoplásicos/farmacología , Compuestos de Boro/química , Línea Celular Tumoral , Hongos/efectos de los fármacos , Bacterias Grampositivas/efectos de los fármacos , Humanos , Inflamasomas/metabolismo , Macrólidos/química , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Bibliotecas de Moléculas Pequeñas/química , EstereoisomerismoRESUMEN
The antibiotic elansolid C1 (8) was isolated from Chitinophaga sancti strain FxGBF13 after fermentation in the presence of anthranilic acid. Remarkably, 8 was also obtained by addition of anthranilic acid to a crude fermentation extract containing the macrolide elansolid A2 (1*). This Michael-type conjugate addition allowed us to generate 21 new derivatives of elansolid C1 (9-29) by using various nucleophiles. Biological activities of all derivatives were evaluated against Staphylococcus aureus, Micrococcus luteus, and the mouse cell line L929.