Dihydrochalcone Glucosides from the Subaerial Parts of Thonningia sanguinea and Their in Vitro PTP1B Inhibitory Activities

Abstract

Six new and four known dihydrochalcone glucoside derivatives (1-10), the phenylpropanoid coniferin (11), and the lignans (+)-pinoresinol (12) and lariciresinol (13) were isolated from the subaerial plant parts of Thonningia sanguinea in the course of a screening campaign for new antidiabetic lead compounds. The structures of the new substances were elucidated by HRESIMS, NMR, GC-MS, and ECD data evaluation. 2'- O-(3-Galloyl-4,6- O- S-hexahydroxydiphenoyl-β-d-glucopyranosyl)-3-hydroxyphloretin (4), 2'- O-(4,6- O- S-hexahydroxydiphenoyl-β-d-glucopyranosyl)phloretin (5), 2'- O-(3- O-galloyl-4,6- O- S-hexahydroxydiphenoyl-β-d-glucopyranosyl)phloretin (6), and thonningianin B (9) showed moderate protein tyrosine phosphatase-1B inhibition in an enzyme assay (IC values ranging from 19 to 25 μM), whereas thonningianin A (10) was identified as a more potent inhibitor (IC = 4.4 μM). The observed activity differences could be explained by molecular docking experiments. The activity of 10 could further be confirmed in HEPG2 liver carcinoma cells, where the compound was able to increase the level of phosphorylated insulin receptors in a concentration-dependent manner.

Development and Validation of a UHPLC-DAD Method for the Quantitative Analysis of Major Dihydrochalcone Glucosides from Thonningia sanguinea VAHL

“…830 bar) with the optimized conditions, which limited the flow rate of the used instrument to 0.4 mL/min. Nevertheless, the analysis time was still reduced (factor 1.8, based on the retention time of thA) compared to conventional HPLC [13] and came with a huge gain in resolution. The compounds in the samples were assigned by comparison of retention times and online LC-UV spectra.…”

“…All three were found to be inhibitors of protein tyrosine phosphatase-1B (PTP1B), a negative regulator in insulin pathway signalling, in an in vitro enzyme assay, whereas the three remaining major compounds, namely, 3-hydroxyphloridzin (1), 2′-O-(6-Ogalloyl-β-D-glucopyranosyl)-3-hydroxyphloretin (2), and 2′-O-(4,6-O-S a -hexahydroxydiphenoyl-β-D-glucopyranosyl)-3-hydroxyphloretin (3), showed no activity. ThA was additionally able to increase the level of phosphorylated insulin receptors in a cell-based assay [13]. Furthermore, thA showed cytotoxic activity on a HepG-2 human hepatocellular carcinoma cell line [14].…”

“…However, this method lacks selectivity, since coelution of the main compounds with smaller peaks in the complex methanol extract was observed, and is rather time-consuming. Moreover, no validation experiments were performed [13]. Therefore, the aim of this study was the development and validation of a UHPLC-DAD method for a quantitative assessment of the major compounds in T. sanguinea subaerial parts, superior to conventional HPLC in terms of selectivity, efficiency, and analysis time.…”

“…All six dihydrochalcone glucoside derivatives (1-4, thB, and thA) were obtained from a previous study and isolated as stated there [13]. Whenever needed, larger amounts of the compounds were re-isolated using the described techniques with slight variations.…”

Purification of thonningianins A and B and four further derivatives from Thonningia sanguinea by one‐ and two‐dimensional centrifugal partition chromatography

“…During an ethnopharmacological survey in the province of Uíge in northern Angola, its various traditional uses have emerged, for example, the use against erectile dysfunction, cough, urinal infections, and as an anthelmintic [4]. In a recent study on this plant, we reported the in vitro pharmacological potential of T. sanguinea and some of its secondary metabolites as inhibitors of protein tyrosine phosphatase 1B (PTP1B) [5], a cellular receptor representing a potential target for the treatment of diabetes, obesity, and some types of cancer [6]. The crude methanol (MeOH) extract of the plant batch investigated in the present study contained six dihydrochalcone glucosides as major compounds, which were identified as thonningianin A (thA), thonningianin B (thB), 3- (4) [5,7].…”