Pharmacokinetics in mice and growth-inhibitory properties of the putative cancer chemopreventive agent resveratrol and the synthetic analogue trans 3,4,5,4′-tetramethoxystilbene

Abstract

Resveratrol (trans-3,5,4 0 -trihydroxystilbene) is a naturally occurring polyphenol with cancer chemopreventive properties in preclinical models of carcinogenesis, including those of colorectal cancer. Recently, a variety of analogues of resveratrol have been synthesised and investigated in in vitro assays. One analogue, 3,4,5,4 0 -tetramethoxystilbene (DMU 212), showed preferential growth-inhibitory and proapoptotic properties in transformed cells, when compared with their untransformed counterparts. As part of a chemoprevention drug development programme, the pharmacokinetic properties of DMU 212 were compared with those of resveratrol in the plasma, liver, kidney, lung, heart, brain and small intestinal and colonic mucosa of mice. DMU 212 or resveratrol (240 mg kg À1 ) were administered intragastrically, and drug concentrations were measured by HPLC. Metabolites were characterised by cochromatography with authentic reference compounds and were identified by mass spectrometry. The ratios of area of plasma or tissue concentration vs time curves of resveratrol over DMU 212 (AUC res /AUC DMU212 ) for the plasma, liver, small intestinal and colonic mucosa were 3.5, 5, 0.1 and 0.15, respectively. Thus, resveratrol afforded significantly higher levels than DMU 212 in the plasma and liver, while DMU 212 exhibited superior availability compared to resveratrol in the small intestine and colon. Resveratrol was metabolised to its sulphate or glucuronate conjugates, while DMU 212 underwent metabolic hydroxylation or single and double O-demethylation. DMU 212 and resveratrol inhibited the growth of human-derived colon cancer cells HCA-7 and HT-29 in vitro with IC 50 values of between 6 and 26 mM. In the light of the superior levels achieved in the gastrointestinal tract after the administration of DMU 212, when compared to resveratrol, the results provide a good rationale to evaluate DMU 212 as a colorectal cancer chemopreventive agent.

Wittig‐Type Olefination of Alcohols Promoted by Nickel Nanoparticles: Synthesis of Polymethoxylated and Polyhydroxylated Stilbenes

“…[22] Such is the case of DMU-212 [(E)-3,4,4Ј,5-tetramethoxystilbene], which has recently disclosed a strong anticancer activity with higher chemoprotective activity than that of resveratrol. [23] As part of our continuous interest in the preparation and 76 application of active metals, [24] we reported the fast synthesis of nickel(0) nanoparticles (NiNPs), from different nickel(II) chloride-containing systems in THF, by using lithium powder and a catalytic amount of an arene, as reducing…”

Resveratrol and Its Analogues – Is It a New Strategy of Anticancer Therapy?

“…The results of the tests conducted by Sale et al [37] point out an increased DMU-212 bioavailability in the small intestine, colonic mucosa and brain as compared to RSV. Higher DMU 212 availability in brain suggests that it overcomes the blood-brain barrier more easily than RSV.…”

“…DMU-212, however, undergoes oxidation in liver, primarily O-demethylation at positions 3,4 or 4 ' and hydroxylation. Sale et al [37] have demonstrated that methylation of hydroxyl groups with RSV and the introduction of new methyl group in position 4 destroys the ability to inhibit COX-2 expression. However, it does not limit the potential for inhibiting the adenomas formation and the ability to reduce PGE-2 level.…”

“…In vivo metabolic demethylation and hydroxylation lead to the creation of five metabolites DMU-212: DMU-214, DMU-281, DMU-291, DMU-295 and DMU-807 which have potential cytotoxic properties [37].…”

4′-Chloro-3,5-dihydroxystilbene, a resveratrol derivative, induces lung cancer cell death

“…In view of resveratrol's anti-tumor potential, it is reasonable to design new chemotherapeutic agents using resveratrol as a prototype. It has been reported that a resveratrol derivative, 3,4,5,4'-tetramethoxystilbene, has stronger anti-proliferative properties in human colon cancer cells [9] . Therefore, we synthesized a series of methoxy groupmodified stilbenes and tested their cytotoxicity in human lung On the other hand, the addition of a halogen group during the structural modification of resveratrol has seldom been reported.…”