Glechomanamides A-C, Germacrane Sesquiterpenoids with an Unusual Δ-7,12-Lactam Moiety from and Their Antiangiogenic Activity.

Three new germacrane sesquiterpenoid-type alkaloids with an unusual Δ-7,12-lactam moiety, glechomanamides A-C (-), and two pairs of 7,12-hemiketal sesquiterpenoid epimers (/, /) were isolated from . Their structures were elucidated by spectroscopic methods including HRESIMS, IR, UV, and 1D and 2D NMR and also confirmed by single-crystal X-ray diffraction analysis. The chemical transformation of compounds - in a solution environment was analyzed by 2D NMR spectroscopy. The aza acetallactams (-) were stable in organic solvent, while single crystals of the hemiacetal esters (/, /) underwent a tautomeric equilibrium after being dissolved. Single crystals of , , and were obtained for the first time as their naturally occurring forms. Glechomanamide B () exhibited antiangiogenic activity by suppression of vascular endothelial growth factor (VEGF)-induced tube formation through modulation of VEGF receptor 2 (VEGFR2)-mediated signaling pathways in human umbilical vascular endothelial cells (HUVECs). In addition, compound also showed the significant suppression of mRNA expression associated with glycolysis and angiogenesis biomarkers in high glucose (30 mM)-induced HUVECs. These findings suggest that compound might be a potential lead compound candidate for the management of diabetic retinopathy.