Three Australian Lepidosperma Labill. Species as sources of prenylated and oxyprenylated derivatives of piceatannol, resveratrol and pinosylvin: Melatoninergic binding and inhibition of quinone reductase 2

Prenylated and hydroxyprenylated piceatannol, resveratrol and pinosylvin derivatives were isolated from resin produced by three Australian Lepidosperma Labill. Species (Cyperaceae). From L. congestum R.Br. one known compound, 3′,5′-bis-prenyl-E-resveratrol, and five undescribed compounds were isolated, 3′-O-prenyl-5′-prenyl-E-piceatannol, 5′,6′-bis-prenyl-E-piceatannol, 5′-prenyl-E-piceatannol, 3′,5′-bis(3-hydroxy-3-methylbutyl)-E-resveratrol and 3′,5′-bis-E-hydroxyprenyl-E-resveratrol. From L. gunnii Boeckeler one undescribed compound was isolated, 3′-E-hydroxyprenyl-5′-Z-hydroxyprenyl-E-resveratrol. From L. laterale R.Br. six undescribed compounds were isolated, 3-O-prenyl-E-pinosylvin, 3-O-Z-hydroxyprenyl-E-pinosylvin, 3′-Z-hydroxyprenyl-E-resveratrol, 3-O-Z-hydroxyprenyl-E-resveratrol, 3-O-Z-hydroxyprenyl-4′-O-methyl-E-resveratrol, and 3-O-prenyl-3′-δ,δ′-dihydroxyprenyl-E-resveratrol. Compounds, including a reference compound 3-O-prenyl-3′-O-methyl-E-piceatannol, were screened in an assay for melatoninergic binding to MT1 and MT2 receptors and binding to QR2/MT3 enzyme, and for inhibition of QR2/MT3 in a functional assay. Strong binding was observed for 3-O-Z-hydroxyprenyl-E-resveratrol with a Ki of 0.022 nM and the strongest inhibition of QR2/MT3 observed was for the reference compound, 3-O-prenyl-3′-O-methyl-E-piceatannol, with an inhibition of 61% at 1 μM and 95% at 10 μM. The three most active binders and inhibitors of QR2/MT3 were found to have a common substructure corresponding to 3-O-prenylresveratrol. Plant constituents’ SAR indicates a substructure for QR2/MT3 inhibition. [Display omitted] •Hydroxyprenylated resveratrols with uncommon combination of E and Z stereochemistry.•Three low micromolar QR2/MT3 inhibitors with 3-O-prenylresveratrol substructure.•A compound binding to QR2/MT3 enzyme with a picomolar Ki value.•12 compounds not previously described from resin of Lepidosperma sedge plants.•4 stilbenoids with Z-stereochemistry of hydroxyprenyl group from L. laterale.