Natural and Semisynthetic Tigliane Diterpenoids with New Carbon Skeletons from Euphorbia dracunculoides as a Wnt Signaling Pathway Inhibitor

Abstract

Euphordraculoates A (1) and B (2), featuring tigliane diterpenoids with two new carbon skeletons, were characterized as metabolites of Euphorbia dracunculoides and semisynthetic products, respectively. Their structures were determined by spectroscopic analyses and X-ray crystallography. The respective biosynthetic and chemical formation mechanisms for 1 and 2 from a known tigliane 3 was proposed. The detailed decarbonization mechanism from 3 to 2 was further explored by O-labeling experiment. Compound 2 could inhibit Wnt pathway in a dose- and time-dependent manner.

Bioactive Compounds from Euphorbia usambarica Pax. with HIV-1 Latency Reversal Activity

“…The OAc and OBz groups should be connected to C-11 and C-12, respectively, based on HMBC correlations ( Figure 3 ). Additionally, comparing the NMR data of 1 with those of euphordraculoate A [ 34 ] suggested the same rare diterpenoid skeleton of both compounds. According to the NOESY cross-peaks between H-8/H-13, H-8/H 3 -18, H-8/H-15, H-9/H 3 -19, 11-OAc/H 3 -19, H-12/H 3 -20, and H-13/H 3 -18, as well as comparing with euphordraculoate A [ 34 ] and euphodendriane A [ 35 ], the relative configuration of 1 was established as shown on structural formula ( Figure 3 ), and the compound was named as euphordraculoate C.…”

“…Additionally, comparing the NMR data of 1 with those of euphordraculoate A [34] suggested the same rare diterpenoid skeleton of both compounds. According to the NOESY cross-peaks between H-8/H-13, H-8/H3-18, H-8/H-15, H-9/H3-19, 11-OAc/H3-19, H-12/H3-20, and H-13/H3-18, as well as comparing with euphordraculoate A [34] and euphodendriane A [35], the relative configuration of 1 was established as shown on structural formula (Figure 3), and the compound was named as euphordraculoate C. 1 and 2) with those of isoterracinolide A (10) [36], the skeleton of 2 was established as a dihomojatrophane type diterpenoid [7] with a double bond at ∆ 11,12 and a lactone moiety. An OH group was located at C-3 based on a 1 H-1 H COSY cross peak between H-3 and 3-OH, as well as the HBMC correlations from 3-OH to C-3 and C-4.…”

“…In this study, 15 new diterpenoids, together with 16 known compounds, were isolated from the dichloromethane phase of methanolic extract of the medicinal plant E. usambarica. Compound 1 exhibited a 6/6/3-fused ring system with an α-methyl-α,β-unsaturated cyclopentanone moiety to construct a rare diterpenoid lactone, this skeleton was the second time discovered from nature [34]. The other compounds could be summarized in 4 types of diterpenoids, including jatrophanes (2-11), tiglianes (12)(13)(14)(15), abietanes (16)(17)(18)(19)(20)(21)(22)(23), and kaurane (24), alone with coumarinolignoid (25), lignan (26), coniferyl acetate (27), and benzenoids (28)(29)(30)(31).…”

Small Molecule Wnt Pathway Modulators from Natural Sources: History, State of the Art and Perspectives

“…Similarly, bisleuconothine A, a bisindole alkaloid with an eburnane-aspidosperma type skeleton, decreased Wnt target gene expression in HCT116 and SW480 colorectal cancer cells through promoting the phosphorylation of β-catenin and the subsequent inhibition of its nuclear translocation; the NP also inhibited cell proliferation in vitro and dramatically suppressed tumor growth in HCT116 mouse xenografts [176]. Natural and semisynthetic tigliane diterpenoids from the plant Euphorbia dracunculoides inhibited Wnt signaling in a luciferase assay in HEK293 cells, reducing the expression of Wnt target genes Axin2, c-myc and cyclin D; phosphorylation and degradation of β-catenin were similarly observed in HEK293W cells incubated with tigliane diterpenoids [177]. Euphorbiaceae plants are otherwise famous for phorbol esters, of which several, of the New Caledonian origin, have produced strong Wnt-inhibiting activities in triple-negative breast cancer cells [152,178].…”

Hot off the Press

“…7 Further new diterpenoid skeletons are found in euphodraculoates A 16 and B 17 from Euphorbia dracunuloides. 8 Biosynthetic pathways from a tigliane precursor to euphodraculoates A 16 and B 17 have been proposed. The structure of lycoplanine A 22, from the club moss Lycopodium complanatum, was established by X-ray analysis.…”