Polyacetylenes from Oplopanax horridus and Panax ginseng: Relationship between Structure and PPARγ Activation

Abstract

Oplopanax horridus and Panax ginseng are members of the plant family Araliaceae, which is rich in structurally diverse polyacetylenes. In this work, we isolated and determined structures of 23 aliphatic C17 and C18 polyacetylenes, of which five are new compounds. Polyacetylenes have a suitable scaffold for binding to PPARγ, a ligand-activated transcription factor involved in metabolic regulation. Using a reporter gene assay, their potential was investigated to activate PPARγ. The majority of the polyacetylenes showed at least some PPARγ activity, among which oplopantriol B 18-acetate (1) and oplopantriol B (2) were the most potent partial PPARγ activators. By employing in silico molecular docking and comparing the activities of structural analogues, features are described that are involved in PPARγ activation, as well as in cytotoxicity. It was found that the type of C-1 to C-2 bond, the polarity of the terminal alkyl chain, and the backbone flexibility can impact bioactivity of polyacetylenes, while diol structures with a C-1 to C-2 double bond showed enhanced cytotoxicity. Since PPARγ activators have antidiabetic and anti-inflammatory properties, the present results may help explain some of the beneficial effects observed in the traditional use of O. horridus extracts. Additionally, they might guide the polyacetylene-based design of future PPARγ partial agonists.

Bioactive C17 and C18 Acetylenic Oxylipins from Terrestrial Plants as Potential Lead Compounds for Anticancer Drug Development

“…The regulation of PPARγ expression in the colon is unresolved but PPARγ expression may be upregulated by intestinal-microbial interactions involving LPS of Gram-negative bacteria and/or ligands of PPARγ [52,211]. A number of acetylenic C 17 and C 18 oxylipins, including falcarinol and falcarindiol have been shown to be ligands of PPARγ and to activate this nuclear receptor [23][24][25]212]. This seems to explain their antidiabetic properties and may contribute to their anti-inflammatory and anticancer activities; thus, an increased expression of PPARγ in epithelial cells would have been expected in rats receiving falcarinol and falcarindiol in the diet.…”

Diterpenoids and Diacetylenes from the Roots of Aralia cordata with Inhibitory Effects on Nitric Oxide Production

“…The UV absorptions at 235, 279, 294, and 314 nm indicated the presence of a diacetylene and a conjugated phenyl moiety. The 1 H NMR data (Table ) exhibited signals for two ( Z )-olefinic protons at δ H 5.63 (dd, J = 10.7, 7.6 Hz, H-10) and 5.53 (dd, J = 10.7, 9.6 Hz, H-9), a terminal vinylic group at δ H 5.81 (ddt, J = 17.2, 10.5, 6.9 Hz, H-16), 5.01 (br d, J = 17.2 Hz, H-17a), and 4.95 (br d, J = 10.5 Hz, H-17b), two oxymethine protons at δ H 5.49 (t, J = 6.5 Hz, H-3) and 5.20 (d, J = 8.3 Hz, H-8), a terminal methyl group at δ H 1.06 (t, J = 7.4 Hz, H-1) together with 12 methylene protons at δ H 1.23–2.11, which resembled the reported data of dehydrofalcarindiol derivatives isolated from Dendropanax arboreus, Gymnaster koraiensis, and Oplopanax horridus . The 13 C NMR and HSQC experiments indicated four nonprotonated alkyne carbons at δ C 79.2, 78.3, 69.3, and 68.9, two olefinic carbons at δ C 134.5 and 127.7, a terminal vinylic group at δ C 139.0 and 114.3, two oxygen-bearing carbons at δ C 65.2 and 58.6, a methyl group at δ C 9.4, and six methylene carbons.…”

CRISPR-Cas9 Genome-Wide Knockout Screen Identifies Mechanism of Selective Activity of Dehydrofalcarinol in Mesenchymal Stem-like Triple-Negative Breast Cancer Cells

“…The ability of some polyacetylenes to act as partial PPARγ agonists has been reported. , Therefore, we evaluated whether the selective cytotoxic activities of 1a could be mediated by their effects on PPARγ. The effects of the PPARγ agonist rosiglitazone were compared to 1a in MDA-MB-231 and MDA-MB-453 cells (Figure S55, Supporting Information).…”