Chemopreventive properties of naturally occurring methoxylated resveratrol analogues

Whereas thousands of papers have been published on the cancer chemopreventive properties of resveratrol (3,5,4′-trihydroxy- trans -stilbene) and related monomeric stilbenoids, there still is no consensus on their mechanism of action in a dietary setting. A widely held assumption is that the naturally occurring trans stilbenoids act as phytoestrogens, and thus affect cell metabolism of estrogen sensitive cells. This is known to be the mechanism of action for Tamoxifen, a synthetic drug with a stilbene moiety at its core, which is now approved as a chemopreventive agent. The bioavailability of resveratrol is low, which means that the doses known to inhibit cell proliferation in vitro (IC 50 in the range 3–30 µM) are never reached in vivo . The cytotoxic activity of a methoxylated analogue of resveratrol, pterostilbene (3,5-dimethoxy-4’-hydroxy trans stilbene), is in the same range as resveratrol. However, the methoxylated trans stilbenoid appears have better pharmacokinetic properties. Still, its overall bioavailability in vivo seems insufficient to make it have any significant effect on modulation of carcinogenesis. Polymethoxylated cis -stilbenoids (combretastatins), in contrast to the trans -stilbenoids, are too cytotoxic to be considered as chemopreventive agents. Combretastatin A4 has been considered as a cancer therapeutic agent; it inhibits tubulin polymerization by interacting at the colchicine binding site of microtubules, a mechanism of action that is fundamentally different from that of the trans -stilbenoids. It may be speculated that naturally occurring trans stilbenoids selectively accumulate in precancerous cells, thus locally reaching sufficiently high levels. This hypothesis may be difficult to prove experimentally. Further clues on the material properties of stilbenoids will most likely come from synthetic chemistry, where a wide range of analogues can be investigated for structure–activity relationships. • Trans -stilbenoids can be considered phytoestrogens. • Trans -stilbenoids can act as chemopreventive agents, preventing development of hormone-dependent tumours. • In vitro assays show little difference in activity between polyhydroxy trans-stilbenoids and their methoxylated analogues. • Polymethoxy cis -stilbenoids are several orders of magnitude more cytotoxic than their trans -analogues. • Methoxylated trans -stilbenoids have better bioavailability than their polyhydroxy analogues.