Resveratrol derivatives as promising chemopreventive agents with improved potency and selectivity.

SCOPE: Despite scores of investigations, the actual impact of resveratrol (3,5,4'-trihydroxy-trans-stilbene) on human health, as a dietary component or supplement, remains moot. This is due to many factors, such as relatively low potency, pleiotropic mechanisms, and rapid metabolism. Nonetheless, as a promiscuous molecule that interacts with numerous targets, resveratrol can be viewed as a scaffold for designing structural relatives potentially capable of mediating more intense responses with greater mechanistic stringency. METHODS AND RESULTS: We currently report the synthesis and biological evaluation of 92 stilbene analogs. The compounds were tested with in vitro assays for activation of quinone reductase 1, inhibition of quinone reductase 2, nitric oxide production, aromatase, NFκB, 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced ornithine decarboxylase, or cyclooxygenase-1 and -2, quenching of 2,2-diphenyl-1-picrylhydrazyl free radical, interaction with estrogen receptors, and as antiproliferative agents. Several compounds were found to mediate responses with much greater potency than resveratrol; some mediated pleiotropic responses, as is the case with the parent molecule, but others were highly specific or totally inactive. When administered to rats, higher serum concentrations and greater stability was demonstrated with prototype lead molecules. CONCLUSION: Owing to structural simplicity, facile syntheses are available for large-scale production. These data support the promise of more advanced development of novel resveratrol derivatives as drug entities.

Bioactive compounds from the fern Lepisorus contortus.

Phytochemical investigation of the whole plant of Lepisorus contortus (Christ) Ching led to the isolation of five new phenylethanoid glycosides (1-5), each containing a caffeoyl group, a new flavonoid glycoside (10), and 14 known compounds (6-9 and 11-15, syringic acid, vanillic acid, phloretic acid, diplopterol, and ß-sitosterol). This is the first report of phenylethanoid glycosides from the family Polypodiaceae. Compounds 1-15 were evaluated for their cancer chemopreventive potential based on their ability to inhibit tumor necrosis factor alpha (TNF-α)-induced NF-κB activity, nitric oxide (NO) production, and aromatase, quinone reductase 2 (QR-2), and COX-1/-2 activities. Quercetin-3-O-ß-d-glucoside (15) demonstrated inhibition against QR2 with an IC(50) value of 3.84 µM, which confirmed kaempferol/quercetin glycosides as the active compounds to inhibit QR2. The compound also demonstrated NF-κB activity with an IC(50) value of 33.6 µM. In addition, compounds 1, 2, 4, and 6 showed aromatase activity with IC(50) values of 30.7, 32.3, 26.8, and 35.3 µM, respectively.