Bioinspired direct diversification of Pinus densiflora resin via an oxa-Diels-Alder reaction and its anti-neuroinflammatory effects in BV2 microglial cells.

The resin of Pinus densiflora (pine resin) serves as a natural reservoir rich in abietane-type diterpenoids, a structurally diverse class of secondary metabolites with notable pharmacological potential. To enhance the structural and biological diversity of diterpenoid-derived compounds, an extract diversification and transformation strategy was employed. Through this approach, a distinct series of unnatural abietane-phloroglucinol meroterpenoids (4a-4g) was generated via a three-component oxa-Diels-Alder reaction using a diterpenoid-enriched fraction as the substrate. The structures of the resulting compounds (4a-4g) were elucidated by comprehensive spectroscopic analyses, including 1D and 2D NMR spectroscopy, mass spectrometry (MS), and electronic circular dichroism (ECD) calculations. Bioactivity screening revealed that compounds 4a and 4c reduced nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells and inhibited inducible nitric oxide synthase (iNOS) expression in a dose-dependent manner. Notably, the newly generated abietane-phloroglucinol meroterpenoids exhibited anti-inflammatory activity compared with the original extract and the individual abietane diterpenoids. These findings highlight the effectiveness of extract diversification as a powerful strategy for unlocking enhanced bioactive potential from natural resources.