Abstract
In a search for anti-inflammatory compounds from fungi inhibiting the promoter activity of the small chemokine CXCL10 (Interferon-inducible protein 10, IP-10) as a pro-inflammatory marker gene, the new dihydroxanthone methyl (1R, 2R)-1,2,8-trihydroxy-6-(hydroxymethyl)-9-oxo-2,9-dihydro-1H-xanthene-1-carboxylate (2) and the previously described dihydroxanthone AGI-B4 (1) were isolated from fermentations of a Diaporthe species. The structures of the compounds were elucidated by a combination of one- and two-dimensional NMR spectroscopy, mass spectrometry, and calculations using density functional theory (DFT). Compounds 1 and 2 inhibited the LPS/IFNγ induced CXCL10 promoter activity in transiently transfected human MonoMac6 cells in a dose-dependent manner with IC50 values of 4.1 µM (±0.2 µM) and 1.0 µM (±0.06 µM) respectively. Moreover, compounds 1 and 2 reduced mRNA levels and synthesis of pro-inflammatory mediators such as cytokines and chemokines in LPS/IFNγ stimulated MonoMac6 cells by interfering with the Stat1 and NFκB pathway.
Funding source: Stiftung Rheinland-Pfalz für Innovation
Funding source: Rhineland Palatinate Natural Products Research Center
Acknowledgments
We thank L. Geske (Mainz) for assistance with chiral HPLC analysis, Dr. J. C. Liermann (Mainz) for NMR spectroscopy, Dr. N. Hanold (Mainz), Dr. C. Kampf (Mainz) for high resolution mass spectrometry as well as Prof. Z. Storchova (Kaiserslautern) for FACS analyses. Parts of this research were conducted using the supercomputer Mogon and/or advisory services offered by Johannes Gutenberg University Mainz (hpc.uni-mainz.de), which is a member of the AHRP (Alliance for High Performance Computing in Rhineland Palatinate, www.ahrp.info) and the Gauss Alliance e.V. The authors gratefully acknowledge the computing time granted on the supercomputer Mogon at Johannes Gutenberg University Mainz (hpc.uni-mainz.de).
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Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
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Research funding: This work was supported by a grant from the Stiftung Rheinland-Pfalz für Innovation and by the Rhineland Palatinate Natural Products Research Center.
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Conflict of interest statement: The authors declare no conflict of interest.
Supplementary Information
Computational details and FACS analyses associated with this paper can be found in the online version of the article.
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Supplementary Material
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