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 Several drugs have been withdrawn from the market or received severe usage restrictions because of hERG-related cardiotoxicity.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.

New Primula-type Flavones from Exudates of Selected Dionysia spp. (Primulaceae)

“…External assistance by microbial endophytes cannot be excluded, as already addressed in our Primula studies [14]. In this context, the parallels of occurrence of oxepinelike structures in both Thymeleaceae [10] and Primula species [14] is a striking feature deserving closer attention.…”

Recent applications of high resolution mass spectrometry for the characterization of plant natural products

“…Following this approach several authors have identified new compounds from vegetal sources in recent years. With the help of ESI-TOF or ESI-Q-TOF, as complementary technique, several classes of new compounds have been characterized including nortriterpenoids [77], unsaturated cyclic ketones [78], daphnane diterpenoid orthoesters and polycephalones [79], sesquiterpenes [80] and bisbibenzyls [81]. Using Orbitrap and LTQ-Orbitrap the exact mass of new compounds, such as triterpenoinds [59], cleordane diterpenoids [82], β-Dihydroagarofuran derivatives [83] and isoflavonoids [84] have been also determined.…”

Natural products modulating the hERG channel: heartaches and hope

“…reduced the hERG channel current by 50.4% and 58.8%, respectively. 69 , 70 From the latter plant material, it is the first time that diterpenes – in this case daphnane-type diterpenoid orthoesters ( 1–3 ) – were identified as hERG channel blockers. …”