hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala

The hERG channel is an important antitarget in safety pharmacology. Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity. In a screening of medicinal plants for hERG channel inhibition using a two-microelectrode voltage clamp assay with Xenopus laevis oocytes, a dichloromethane extract of the roots of Gnidia polycephala reduced the peak tail hERG current by 58.8 +/- 13.4% (n = 3) at a concentration of 100 mu g/mL. By means of HPLC-based activity profiling daphnane-type diterpenoid orthoesters (DDOs) 1, 4, and 5 were identified as the active compounds [55.4 +/- 7.0% (n = 4), 42.5 +/- 16.0% (n = 3), and 51.3 +/- 9.4% (n = 4), respectively, at 100 mu M]. In a detailed phytochemical profiling of the active extract, 16 compounds were isolated and characterized, including two 2-phenylpyranones (15 and 16) with an unprecedented tetrahydro-4H-5,8-epoxypyrano[2,3-d]oxepin-4-one skeleton, two new DDOs (3 and 4), two new guaiane sesquiterpenoids (11 and 12), and 10 known compounds (1, 2, 5-10, 13, and 14). Structure elucidation was achieved by extensive spectroscopic analysis (1D and 2D NMR, HEMS, and electronic circular dichroism), computational methods, and X-ray crystallography.