Pyrenoids A-P: Ring-Rearranged Tropolonic Sesquiterpenoids with Anti-Neuroinflammatory Effects from the Marine...

Sixteen new ring-rearranged tropolonic sesquiterpenoids, pyrenoids A-P (1-16), along with four known congeners (17-20), were isolated from the fungus Pyrenochaeta sp. associated with the mesophotic sponge Cinachyrella 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 (1-10) are sesquiterpene-tropolone hybrids featuring a ring-rearranged tropolone moiety that forms a new 5/5 bicyclic system. In contrast, pyrenoid K (11) 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 (3) dose-dependently suppressed lipopolysaccharide (LPS)-induced production of NO and pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) 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.