Substituted trans-Stilbenes, Including Analogues of the Natural Product Resveratrol, Inhibit the Human Tumor Necrosis Factor Alpha-Induced Activation of Transcription Factor Nuclear Factor KappaB

Abstract

The transcription factor nuclear factor kappaB (NF-kappaB), which regulates expression of numerous antiinflammatory genes as well as genes that promote development of the prosurvival, antiapoptotic state is up-regulated in many cancer cells. The natural product resveratrol, a polyphenolic trans-stilbene, has numerous biological activities and is a known inhibitor of activation of NF-kappaB, which may account for some of its biological activities. Resveratrol exhibits activity against a wide variety of cancer cells and has demonstrated activity as a cancer chemopreventive against all stages, i.e., initiation, promotion, and progression. The biological activities of resveratrol are often ascribed to its antioxidant activity. Both antioxidant activity and biological activities of analogues of resveratrol depend upon the number and location of the hydroxy groups. In the present study, phenolic analogues of resveratrol and a series of substituted trans-stilbenes without hydroxy groups were compared with resveratrol for their abilities to inhibit the human tumor necrosis factor alpha-induced (TNF-alpha) activation of NF-kappaB, using the Panomics NF-kappaB stable reporter cell line 293/NF-kappaB-luc. A series of 75 compounds was screened to identify substituted trans-stilbenes that were more active than resveratrol. Dose-response studies of the most active compounds were carried out to obtain IC50 values. Numerous compounds were identified that were more active than resveratrol, including compounds that were devoid of hydroxy groups and were 100-fold more potent than resveratrol. The substituted trans-stilbenes that were potent inhibitors of the activation of NFkappaB generally did not exhibit antioxidant activity. The results from screening were confirmed using BV-2 microglial cells where resveratrol and analogues were shown to inhibit LPS-induced COX-2 expression.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…Resveratrol has been found to modulate neuroinflammation in both in vivo and in vitro models, specifically targeting activated micloglial cells [71]. Actually, resveratrol suppresses the activation of the NF-kB pathway in LPS-activated microglia by reducing the phosphorylation and consequent degradation of its inhibitor, IkB [72][73][74][75]. Our results demonstrate that microglial, but not astroglial reactivity, was significantly diminished with resveratrol administration compared to untreated SOD1 G93A mice.…”

Inhibitory effect of cytotoxic stilbenes related to resveratrol on the expression of the VEGF, hTERT and c-Myc genes

“…The various biological activities of resveratrol analogues depend upon the number and location of the hydroxy groups [34], minor structural changes in such stilbenes having major effects on their biological activity [35]. In the present study, a series of 39 stilbenes carrying hydroxy, methoxy and amino groups were compared with resveratrol for their cytotoxicity and for their ability to inhibit VEGF secretion and the expression of the VEGF, h-TERT and c-Myc genes.…”

Synthesis of Pyronyl Derivatives as Resveratrol Analogues and Their Inhibitory Effects on Nitric Oxide and PGE2Productions

“…[10][11] However, due to its low oral bioavailability 12 and the relatively high concentrations of resveratrol which are required to exert anti-inflammatory activity, 13 the modifications of the structure of resveratrol were desired to produce more efficient anti-inflammatory agents. In fact, there has been a number of reports on the synthesis of resveratrol analogues, such as hydroxystilbenes, [14][15][16][17] styrylthiophenes, styrylpyridines, and styrylquinolines. 18 We also reported the synthesis of styrylquinazolines as resveratrol analogues and their ability to inhibit the production of PGE 2 in LPS-activated macrophage cells.…”