title: 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).
authors.affiliation: National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, Mississippi 38677, United States.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Zaki
authors.forename: Premalatha
authors.initials: P
authors.lastname: Balachandran
authors.forename: Shabana
authors.initials: S
authors.lastname: Khan
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.forename: Rabab
authors.initials: R
authors.lastname: Mohammed
authors.forename: Mona H
authors.initials: MH
authors.lastname: Hetta
authors.forename: David S
authors.initials: DS
authors.lastname: Pasco
authors.forename: Ilias
authors.initials: I
authors.lastname: Muhammad
mesh_terms: D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D000975:Antioxidants / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D016328:NF-kappa B / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors; D019906:Nuclear Magnetic Resonance, Biomolecular; D018515:Plant Leaves / Q000737:chemistry; D011647:Puerto Rico; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D013237:Stereoisomerism; D013267:Stilbenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D027842:Syzygium / Q000737:chemistry*
chemical_list: C582759:(E)-3,4,3',5'-tetramethoxystilbene; C582760:(E)-3,5,4'-trimethoxystilbene; C582758:(Z)-3,4,3',5'-tetramethoxystilbene; D000972:Antineoplastic Agents, Phytogenic; D000975:Antioxidants; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013267:Stilbenes; C041525:3,3',4,5'-tetrahydroxystilbene; D052247:Nitric Oxide Synthase Type II