Cytotoxicity and Modulation of Cancer-Related Signaling by (Z)- and (E)-3,4,3′,5′-Tetramethoxystilbene Isolated from Eugenia rigida

Abstract

Bioassay-guided fractionation of the leaves of Eugenia rigida yielded three stilbenes, (Z)-3,4,3',5'-tetramethoxystilbene (1), (E)-3,4,3',5'-tetramethoxystilbene (2), and (E)-3,5,4'-trimethoxystilbene (3). Their structures were determined using 1D- and 2D-NMR spectroscopy and HRESIMS. The sterically hindered Z-stereoisomer 1, a new natural product, was prepared by time-dependent photoisomerization of the E-isomer (2) under UV irradiation at λ254 nm, while 2,3,5,7-tetramethoxyphenanthrene (5) was identified at λ365 nm by UHPLC/APCI-MS and NMR spectroscopy. Compounds 1-3 were tested against a panel of luciferase reporter gene assays that assess the activity of many cancer-related signaling pathways, and the Z-isomer (1) was found to be more potent than the E-isomer (2) in inhibiting the activation of Stat3, Smad3/4, myc, Ets, Notch, and Wnt signaling, with IC50 values between 40 and 80 μM. However, both compounds showed similar inhibition against Ap-1 and NF-κB signaling. In addition, 1 demonstrated cytotoxic activity toward human leukemia cells, solid tumor cells of epidermal, breast, and cervical carcinomas, and skin melanoma, with IC50 values between 3.6 and 4.3 μM, while 2 was weakly active against leukemia, cervical carcinoma, and skin melanoma cells. Interestingly, 2 showed antioxidant activity by inhibition of ROS generation to 50% at 33.3 μM in PMA-induced HL-60 cells, while 1 was inactive at 100 μM (vs Trolox 1.4 μM).

Anti-tumor properties of cis-resveratrol methylated analogs in metastatic mouse melanoma cells

“…Each mixture was resolved by silica gel PLC column chromatography using a gradient of EtOAc- n -hexane to separate the Z product from the residual E isomer. Spectral data of compounds 5 - 8 are in perfect agreement with those reported in the literature (35-37). …”

Diversity-oriented natural product platform identifies plant constituents targeting Plasmodium falciparum

“…This plant, present in Brazil and Argentina and distributed in the Caribbean islands, has been used traditionally for the treatment of leukaemias. Earlier investigation of E. rigida exhibited ( E )- and ( Z )-3,4,3′,5′-tetramethoxystilbenes and 4,3′,5′-trimethoxyresveratrol with cytotoxic and cancer-related signal-modulating activities [ 26 ]. The crude ethanolic extract was inactive in the initial screens against P. falciparum , but the AHTS-derived COMBI 79575-c5 had potent activity against 3D7 and K1 strains, with respective EC 50 values of 0.6 and 0.19 µg/mL; other COMBIs were inactive.…”

The Anti-Proliferative Activity of the Hybrid TMS-TMF-4f Compound Against Human Cervical Cancer Involves Apoptosis Mediated by STAT3 Inactivation

“…Although we previously reported the synthesis of TMS and TMF hybrid analogs and their growth inhibitory effects on various cancer cells [16], only percent growth inhibition values were determined. In this study, we examined the mechanism involved in the cytotoxicity of hybrid TMS-TMF compounds in human cervical carcinoma cells.…”

“…The molecular hybridization of anti-cancer agents is an effective strategy to generate novel ligands with improved anti-cancer activity relative to the parent molecules [13][14][15][16]. By adopting this strategy, we recently reported the synthesis of natural product hybrids that could induce potential anti-proliferative activity [16].…”

“…The molecular hybridization of anti-cancer agents is an effective strategy to generate novel ligands with improved anti-cancer activity relative to the parent molecules [13][14][15][16]. By adopting this strategy, we recently reported the synthesis of natural product hybrids that could induce potential anti-proliferative activity [16]. We hybridized 3,5,4 -trimethoxystilbene (TMS), which is a permethylated analog of resveratrol, with 5,6,7-trimethoxyflavone (TMF), which is a flavone derivative whose anti-cancer activity is triggered by nuclear factor-kappa B (NF-кB) suppression [17][18][19].…”