Unusual ent-Labdane Diterpenoid Dimers and their Selective Activation of TRPV Channels

Five unusual dimers of ent-labdane diterpenoids (1–5) were isolated and identified from Andrographis paniculata, a famous medicinal plant. Bisandrographolide E (1) represents the first example of a labdane dimer possessing an unprecedent tricyclic system that comprised a spiroketal moiety fused with a ketal-γ-lactone unit in its skeleton. Its biosynthetically related intermediates, all four stereoisomers at C-12 and C-15′, bisandrographolides F (2, a new compound) and A–C (3–5), were obtained at the same time. The steric configurations of the newly formed asymmetric carbons in 1–5 were first solved by single-crystal X-ray diffraction of the diacetone derivatives of 2–4 and ECD and NMR calculations of 1. More importantly, bisandrographolides 1–5, with different chemical structures or absolute configurations at C-12 and C-15′, selectively activated different TRPV1–4 channels and protected cardiomyocytes from hypoxia-reoxygenation injury. Among them, 5 with 12R/15′S configuration activated TRPV1 most effectively and displayed the best cardiomyocyte protection.