title: hERG Channel Inhibitory Daphnane Diterpenoid Orthoesters and Polycephalones A and B with Unprecedented Skeletons from Gnidia polycephala.
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 Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity.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 μg/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 μM]. 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, HRMS, and electronic circular dichroism), computational methods, and X-ray crystallography.
authors.forename: Maria
authors.initials: M
authors.lastname: De Mieri
authors.forename: Kun
authors.initials: K
authors.lastname: Du
authors.forename: Markus
authors.initials: M
authors.lastname: Neuburger
authors.affiliation: ⊥Institute of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Priyanka
authors.initials: P
authors.lastname: Saxena
authors.affiliation: ||National Museum, P.O. Box 266, Bloemfontein 9300, South Africa.
authors.forename: Pieter C
authors.initials: PC
authors.lastname: Zietsman
authors.affiliation: ⊥Institute of Pharmacology and Toxicology, University of Vienna, Althanstrasse 14, A-1090 Vienna, Austria.
authors.forename: Steffen
authors.initials: S
authors.lastname: Hering
authors.forename: Jan H
authors.initials: JH
authors.lastname: van der Westhuizen
authors.forename: Matthias
authors.initials: M
authors.lastname: Hamburger
mesh_terms: D000818:Animals; D001584:Benzoxepins / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D004224:Diterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009865:Oocytes / Q000187:drug effects; D013019:South Africa; D029645:Thymelaeaceae / Q000737:chemistry*; D014981:Xenopus
chemical_list: D001584:Benzoxepins; D004224:Diterpenes; D051638:Ether-A-Go-Go Potassium Channels; C000602212:polycephalone A; C000602213:polycephalone B; C011309:mezerein