Discovery of structurally intriguing diterpenoids as anti-neuroinflammatory agents from mangrove plant Excoecaria agallocha L. via inhibiting macrophage polarization and inflammasome.

Emerging evidence indicates the inhibition of neuroinflammation is an important and promising strategy for managing Alzheimer's disease. Anti-neuroinflammatory agents are potential drug leads. In this work, seventeen diterpenoids (1-17) including ten previously undescribed ones, named excoaglolides A-J (1-10) were isolated from the stems and twigs of the mangrove plant, Excoecaria agallocha L. The undescribed diterpenoids could be categorized into four subclasses, viz., ent-isopimaranes (1-4), ent-beyeranes (5-7), ent-atisanes (8-9), and ent-labdane (10). Their structures including absolute configurations were unambiguously characterized by spectroscopic methods, single crystal X-ray diffraction analyses, ECD calculations, and modified Mosher's method. Notably, compound 1 was a rare 3,4-seco-3,11-lactone-ent-isopimarane, whereas compound 2 was the first 2,3-seco-2,11-lactone-ent-isopimarane; compound 5 represents the first example of 2,3-seco-2-nor-1,3-lactone-ent-beyerane, compound 8 was the first member of 18(4 → 3)-abeo-ent-atisane forming through a Wagner-Meerwein rearrangement, compound 9 was an unusual rearranged 3,4-seco-ent-atisane possessing a cyclobutane ring, and compound 10 featuring a rare chlorine substitution at C-15. In addition, the stereochemistry of the known diterpenoid excoagallochaol D (11) with a unique 6/7/4-fused ring system was firstly determined by single crystal X-ray diffraction analyses in this study. Compounds 1, 12, 15, and 16 showed significant nitric oxide production inhibition in lipopolysaccharide-induced BV-2 microglial cells with IC values ranging from 2.0 to 13.5 μM. Further mechanistic investigations revealed that compound 1 inhibited macrophage polarization and decreased the expression levels of representative inflammation-related genes, including IL-1β, IL-6, TNF-α, COX-2, and iNOS. These were associated with suppressions of proteins related to inflammasome, including caspase 1 and NLRP3, and secretion of IL-1β. The present study revealed that the mangrove diterpenoid excoaglolide A (1) would be promising structure base for developing neuroinflammation-related neurodegeneration diseases.