Resveratrol analog (Z)‐3,5,4′‐trimethoxystilbene is a potent anti‐mitotic drug inhibiting tubulin polymerization

Abstract

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...

Different apoptotic mechanisms are involved in the antiproliferative effects of 7β-hydroxysitosterol and 7β-hydroxycholesterol in human colon cancer cells

“…66 In brief, 1 Â 10 6 were seeded in 10 mm plates, treated with hydroxysterols or ethanol and at each time point, cells were collected by trypsinization and centrifugation, and then stored at À801C. Apoptotic DNA was recovered from cells by using the Suicide Trackt DNA ladder kit (Oncogene Research Products, Cambridge, UK).…”

Suppression of human monocyte tissue factor induction by red wine phenolics and synthetic derivatives of resveratrol

“…Resveratrol derivatives were synthesized as described earlier [23,25]. Recombinant factor VIIa was a kind gift from Novo Nordisk (Copenhagen, Denmark).…”

“…In most of the studies described above, relatively high concentrations of resveratrol (10 to 100 µM range) were required to modulate various cellular effects. In order to improve the efficacy of the resveratrol, with the aim of discovering new lead compounds with the clinical treatment potential, a series of cis-and trans-stilbene-based resveratrols were synthesized [23][24][25]. Of the compounds tested for the anti-proliferative and apoptotic activity on HL60 promyelocytic leukemia cells, cis-3, 4′ , 5-trimethoxy-3′ -aminostilbene (7b) and cis-3, 4′, 5-trimethoxy-3′-hydroxystilbene (11b) were effective at the nanomolar concentrations [23].…”

“…Of the compounds tested for the anti-proliferative and apoptotic activity on HL60 promyelocytic leukemia cells, cis-3, 4′ , 5-trimethoxy-3′ -aminostilbene (7b) and cis-3, 4′, 5-trimethoxy-3′-hydroxystilbene (11b) were effective at the nanomolar concentrations [23]. Resveratrol derivative, R3 (cis-Z-3, 5, 4′ -trimethoxystilbene) was shown to be 100-fold more active than resveratrol in causing cell cycle arrest in colon cancer cells [25].…”

“…Further, we have tested for the first time, whether chemically modified derivatives of resveratrol, which were shown to be highly effective in inhibiting cancer cell proliferation than resveratrol [23,25], could inhibit LPS-induced TF expression in peripheral blood mononuclear cells at much lower doses than resveratrol.…”