Ent-pimarane and ent-kaurane diterpenoids from Siegesbeckia pubescens and their anti-endothelial damage effect in diabetic retinopathy

Diabetic retinopathy is a common and sight-threatening microvascular complication of diabetes mellitus that accounts for the leading cause of blindness among middle-aged and elderly people. Natural diterpenoids isolated from Siegesbeckia pubescens have potent anti-inflammatory properties. In this study, we aimed to search for new bioactive diterpenoids from S. pubescens and investigate their effect on oxidative stress and inflammatory responses both in vitro and in vivo in diabetic retinopathy. Three new ent-pimarane-type diterpenoids (1–3) along with six known compounds (4–9) were isolated from the aerial parts of S. pubescens. Their structures were elucidated on the basis of spectroscopic data interpretation. The absolute configurations were determined based on the comparison of calculated and experimental ECD spectra. Among these compounds, 14β,16-epoxy-ent-3β,15α,19-trihydroxypimar-7-ene (5) exhibited the most potent protective effect against high glucose and IL-1β-stimulated human retinal endothelial cells. Mechanically, compound 5 promoted endothelial cell survival while ameliorating oxidative stress and inflammatory response both in vivo and in vitro in diabetic retinopathy. These findings not only suggest that diterpenoids such as 14β,16-epoxy-ent-3β,15α,19-trihydroxypimar-7-ene (5) are the important anti-inflammatory constituents in S. pubescens, but also indicate that compound 5 may serve as a lead compound for preventing or treating vascular complications associated with diabetic retinopathy.