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Title: Cytotoxicity and modulation of cancer-related signaling by (Z)- and (E)- 3,4,3´,5´ tetramethoxystilbene isolated from Eugenia rigida

Author
item MOHAMED, ZAKI - University Of Mississippi
item BALACHANDRAN, PREMALATHA - University Of Mississippi
item KHAN, SHABANA - University Of Mississippi
item WANG, MEI - University Of Mississippi
item MOHAMMED, RABAB - University Of Mississippi
item HETTA, MONA - University Of Mississippi
item PASCO, DAVID - University Of Mississippi
item MUHAMMAD, ILIAS - University Of Mississippi

Submitted to: Journal of Natural Products
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/15/2013
Publication Date: 4/2/2013
Citation: Mohamed, Z., Balachandran, P., Khan, S., Wang, M., Mohammed, R., Hetta, M.H., Pasco, D.S., Muhammad, I. 2013. Cytotoxicity and modulation of cancer-related signaling by (Z)- and (E)- 3,4,3´,5´ tetramethoxystilbene isolated from Eugenia rigida. Journal of Natural Products. 76:679–684.

Interpretive Summary: Bioassay- guided fractionation of the leaves of Eugenia rigida yielded three stilbenes, namely Z-3,3´4,5´-tetramethoxystilbene (1), E-3,3´4,5´-tetramethoxystilbene (2) and E-3,4´,5-trimethoxystilbene (3). Their structures were determined using NMR spectroscopy. Compounds 1-3 were tested to assess the activity of many cancer-related signaling pathways. Z-isomer (1), an new compound, was found to be more potent than E- isomer (2) at inhibiting the activation of some enzymes involved in cancer. However, both compounds showed similar inhibition against other enzymes. In addition, 1 demonstrated cytotoxic activity towards human leukemia cells, as well as solid tumor cells of epidermal, breast and cervical carcinomas, and skin melanoma, while 2 was weakly active against leukemia, cervical, and skin melanoma cells. Interestingly, 2 showed antioxidant activity.

Technical Abstract: The leaves of E. rigida DC (Myrtaceae) were collected from Puerto Rico in March, 2006. The sample was identified by Mr. F. Axelrod and a voucher specimen (3008783) was deposited at the Herbarium of Missouri Botanical Garden, St. Louis, MO. Air-dried powdered leaves (107 g) were soaked in n-hexane and sonicated (600 ml x 3 x 2 h each). The combined extract was filtered and dried (2.5 g), and the residue was extracted with CH2Cl2, followed by EtOAc and MeOH, as executed for n-hexane, yielding 3.8, 1.1 and 14.0 g, respectively. The hexane extract fraction demonstrated cytotoxic activity. The hexane extract (2 g) was subjected to centrifugal preparative TLC (CPTLC, Chromatotron®), using a 6 mm custom made reversed phase ChromatorotorTM packed with binder free C18 silica gel. The rotor was mounted on a Chromatotron®, and packed under slow rotation (100 rpm) by applying a slurry of C18 SiO2 (100 g) doped with UV 254 and 365 fluorescent indicators (0.5% each) in H2O-MeOH (1:9; 300 mL). The sample, dissolved in Me2CO, was applied to the rotor under a rotation of 700 rpm, and then the rotor was removed from instrument and left for drying in a desecrator. The dried rotor was mounted on Chromatotron® and eluted with H2O-MeOH (3:7), which afforded fr. 12-21 (174 mg) containing a mixture of compounds 1-3. This fraction was subjected to CPTLC, using a 2 mm silica gel disc, and eluted with 0.5 - 20% Me2CO in n-hexane, which afforded compound 1 (3 mg), followed by 2 (30 mg) and 3 (1 mg), respectively, as monitored and pooled by TLC analyses (silica gel, solvent: toluene: EtOAc 9:1).