Pyrenoids A-P: Ring-Rearranged Tropolonic Sesquiterpenoids with Anti-Neuroinflammatory Effects from the Marine Mesophotic Sponge-Associated Fungus Pyrenochaeta sp. NBUF199.

Sixteen new ring-rearranged tropolonic sesquiterpenoids, pyrenoids A-P (-), along with four known congeners (-), were isolated from the fungus sp. associated with the mesophotic sponge sp. at a depth of 71.8 m. Their structures were elucidated by detailed spectroscopic analysis, single-crystal X-ray diffraction studies, and quantum chemical calculations. Pyrenoids A-J (-) are sesquiterpene-tropolone hybrids featuring a ring-rearranged tropolone moiety that forms a new 5/5 bicyclic system. In contrast, pyrenoid K () possesses a new ring-contracted framework resulting from the transformation of a seven-membered ring to a five-membered tropolone unit. Biological evaluation revealed that pyrenoid C () dose-dependently suppressed lipopolysaccharide (LPS)-induced production of NO and pro-inflammatory cytokines (IL-1, IL-6, and TNF-) in BV-2 microglial cells at noncytotoxic concentrations. Further mechanistic investigations, guided by transcriptomic profiling, indicated that this antineuroinflammatory effect is mediated through the suppression of NF-κB signaling by inhibiting p65 phosphorylation at Ser536 and its nuclear translocation.