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hERG channel inhibitory daphnane diterpenoid orthoesters and polycephalones A and B with unprecedented skeletons from Gnidia polycephala
Journal
Journal of natural products
Volume
78
Number
7
Pages / Article-Number
1697-707
Abstract
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 Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity.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.
