Resveratrol (3,5,4Ј-trihydroxystilbene) is a natural polyphenol present in a variety of medicinal plants and in grapes. 1 Its function is to protect plants against pathogenic attack and environmental stress. 2,3 Because of its production by grape skin, significant amounts are found in red wines. 4 First evidence of the beneficial effects of resveratrol for human health was shown by its ability to protect against cardiovascular diseases. Resveratrol exhibits strong antioxydant activity 5,6 and inhibits platelet aggregation. 7,8 More recently, numerous cancer chemopreventive properties of resveratrol have been demonstrated . 9 -12 Ptero-stilbene, a derivative of resveratrol that is methylated at positions 3 and 5, exhibits greater antifungal activity than resveratrol. 13,14 However, this molecule is only present in very low concentrations in grapes and seems to be a minor effector of the plant defensive response. It has been shown that methylated derivatives of flavonoïds exhibit higher antiproliferative potency on cancer cells than their hydroxylated counterparts. 15 This ability may be related to the increased lipophilic properties of the methoxyflavonoids and their increased uptake through the cell membrane. On this basis we have developed a methylated derivative of resveratrol (R3: Z-3,5,4Ј-trimethoxystilbene; Fig. 1) with the aim to evaluate its antiproliferative effects on the human colon cancer cell line Caco-2.Previously resveratrol was shown to inhibit the proliferation of Caco-2 cells through the accumulation of cells in the S phase of the cell cycle and by inhibiting polyamine biosynthesis. 16 The effects of resveratrol were not cytotoxic but mainly cytostatic and reversible. In the present study, we show that R3 exerts a 100-fold higher inhibitory effect on colon cancer cell growth. The growth supressive effects induced by R3 were totally different from those observed with resveratrol and were related to a selective blockade of cells at the G2/M phase of the cell cycle, and to the disruption of the microtubule network. MATERIAL AND METHODS Synthesis of (Z)-3,5,4.ЈЈ-trimethoxystilbene (R3)The compound was synthesized by a Wittig-Horner reaction from 4-methoxybenzyl-diethyl phosphonate and 3,5-dimethoxybenzaldehyde 17,18 (Fig. 2). All reagents were commercially available and used without further purification.Melting points were measured without correction in capillary tubes on a Büchi apparatus.1 H and 13 C NMR spectra were recorded on a Bruker AC 200 MHz spectrometer. Mass spectra were established on a Fisons spectrometer at 70 eV chamber voltage, using a direct inlet tube. Silica gel 60 (40 -63 mesh, Merck Eurolab SA, Strasbourg, France) and thin layer chromatography with aluminium sheets 20 ϫ 20 cm 60 F 254 (Merck Eurolab SA, Strasbourg, France) were used. Dimethylformamide was distilled over 0.4 nm molecular sieves under reduced pressure prior to its use; 4-Methoxybenzyl alcohol (1) was purchased from Acros (Noisy le Grand, France), 3,5-dimethoxybenzaldehyde from Avocado (La Tour du Pin, France) an...

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Over the past few years, it has been accepted that a moderate red wine consumption is a factor beneficial to human health. Indeed, people of France and Italy, the two major wine-producing European countries, eat a lot of fatty foods but suffer less from fatal heart strokes than people in North-America or in the northern regions of Europe, where wine is not consumed on a regular basis. For a time, ethanol was thought to be the "good" chemical species hiding behind what is known as the "French paradox". Researchers now have turned their investigations towards a family of natural substances called "polyphenols", which are only found in plants and are abundant in grapes. It is well known that these molecules behave as radical scavengers and antioxidants, and it has been demonstrated that they can protect cholesterol in the LDL species from oxidation, a process thought to be at the origin of many fatal heart attacks. However, taken one by one, it remains difficult to demonstrate which are the best polyphenols as far as their antioxidant activities are concerned. The main obstacle in that kind of research is not the design of the chemical and biological tests themselves, but surprisingly enough, the limited access to chemically pure and structurally elucidated polyphenolic compounds. In this article, particular attention will be paid to polyphenols of red wine made from Vitis vinifera cultivars. With respect to the "French paradox", we address the following question: are wine polyphenolic compounds identical to those found in grapes (skin, pulp and seed), or are there biochemical modifications specifically taking place on the native flavonoids when a wine ages? Indeed, structural changes occur during wine conservation, and one of the most studied of those changes concerns red wine colour evolution, called "wine ageing". As a wine ages, it has been demonstrated that the initially present grape pigments slowly turn into new more stable red pigments. That phenomenon goes on for weeks, months and years. Since grape and wine polyphenols are chemically distinct, their antioxidant activities cannot be the same. So, eating grapes might well lead to beneficial effects on human health, due to the variety and sometimes large amounts of their polyphenolic content. However, epidemiological surveys have focused on wines, not on grapes....

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(Z)-3,5,4'-Trimethoxystilbene is a natural polyphenol present in five different plants, Virola cuspidata, Virola elongata, Centipeda minima, Schoenus nigricans and Rheum undulatum. This molecule was prepared in a three-step sequence in good overall yield. The isomerisation from the (E)- to (Z)-isomer is performed using UV irradiation. Biological investigations were conducted on a human colon cancer cell line (Caco-2) with anti-mitotic activities. Growth was completely arrested at an added 0.4 microM level of (Z)-3,5,4'-trimethoxystilbene. This agent is 100-fold more active than resveratrol or (E)-3,5,4'-trihydroxystilbene, and the mechanism of this process involves an inhibition of tubulin polymerisation in a dose dependent manner.