Diketopiperazines with anti-skin inflammation from marine-derived endophytic fungus Aspergillus sp. and configurational reassignment of aspertryptanthrins

Two novel diketopiperazines (1 and 5), alongside ten known ones (2−4, 6−12) exhibiting significant inhibition of skin inflammation, were isolated from a marine-derived fungus identified as Aspergillus sp. FAZW0001. The structural elucidation and configurational reassessments of compounds 1−5 were established utilizing comprehensive spectral methodologies, while their absolute configurations were determined via single crystal X-ray diffraction using Cu Kα radiation, Marfey’s method, and comparison between experimental and calculated ECD spectra. Compounds 1, 2, and 8 demonstrated noteworthy anti-inflammatory activities on Propionibacterium acnes-induced human monocyte cell lines. Compound 8 exhibited the capability to down-regulate the expression of IL-1β by inhibiting TLR2 expression and modulating the activation of MyD88, MAPK, and NF-κB signaling pathways, thereby mitigating the cellular inflammatory response induced by P. acnes. Furthermore, compound 8 manifested the ability to impede the production of mitochondrial ROS and the activation of NLRP3 inflammasomes, thereby attenuating the maturation and secretion of IL-1β. Finally, the three-dimensional quantitative structure-activity relationships (3D-QSAR) model was applied to compounds 5−12 to analyze their anti-inflammatory structure-activity relationships.