Selected references of Resveratrol analogues
The enzyme cyclooxygenase (COX) catalyzes the first two steps in the biosynthesis of prostaglandins (PGs) from the substrate arachidonic acid. At least two forms of this enzyme exist. One of these forms, COX-1, is constitutively expressed and is responsible for maintaining normal physiologic function and the PGs produced by this enzyme play a protective role. The other known form of the enzyme, cyclooxygenase-2 (COX-2), is an inducible form and its expression is affected by various stimuli such as mitogens, oncogenes, tumor promoters and growth factors.
COX-2 is the principal isoform that participates in inflammation, and induction of COX-2 is responsible for the production of PGs at the site of inflammation. Consequently, selective inhibition of COX-2 should have therapeutic actions similar to those of non- al anti-inflammatory drugs (NSAIDs), but without gastrointestinal side effects, which are being caused as a consequence of COX-1 inhibition. Several selective COX-2 inhibitors are currently used in the clinics (e.g. celecoxib, valdecoxib, parecoxib, rofecoxib, etoricoxib, and lumiracoxib) which provide effective treatment of inflammatory disease states such as rheumatoid arthritis and osteoarthritis.3 Several lines of evidence suggest that selective COX-2 inhibitors may also provide an opportunity for both cancer prevention and therapy. Furthermore, promising in vitro data also indicate that treatment with selective COX-2 inhibitors may also reduce the risk of Alzheimer’s and Parkinson’s disease.and may also be effective in the treatment of asthma.
Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a phytoalexin found mainly in the skin of grapes and red wine and demonstrates anti-inflammatory, cardiovascular protective, and cancer chemopreventive properties.10 It has also been shown to be a non-selective inhibitor of COX-1 and COX-2. In vitro and in vivo, resveratrol is extensively metabolized to several glucuronides and sulfates.12,13 Moreover, resveratrol undergoes cytochrome P450 catalyzed hydroxylation to piceantannol, 3,4,4’,5-tetrahydroxy-trans-stilbene, and to two other unidentified mono- and dihydroxyresveratrol analogues. As piceatannol15 demonstrates a several fold higher antileukaemic activity than resveratrol and as COX-2 is a known target for anticancer activity we investigated whether piceatannol and other hydroxylated resveratrol analogues might achieve a better and more selective COX-2 inhibition than resveratrol. Five hydroxy and six methoxy analogues of resveratrol were therefore synthesized using standard chemical methods. Each analogue was then tested for COX-1 and COX-2 inhibition in an in vitro model and the resulting inhibition values compared with that of resveratrol and the clinically established selective COX-2 inhibitor celecoxib. In addition, a quantitative structure–activity relationship (QSAR) study was being conducted to evaluate the effects of various structural parameters of the molecules on COX-1 and COX-2 inhibition.
Bioorganic & Medicinal Chemistry 12 (2004) 5571–5578
In the pathogenesis of atherosclerosis, growing evidence suggests that free-radical-induced oxidative modification of low density lipoprotein (LDL) may be involved. Therefore, inhibition of LDL peroxidation by addition of antioxidants becomes an attractive therapeutic strategy to prevent and possibly to treat atherosclerosis and related diseases in human. This leads to a great deal of research devoted to the prevention of lipid peroxidation of LDL by antioxidants.
Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a naturally occurring phytoalexin present in grapes, nuts and other plants. It is believed that the high level of this compound in red wine (0.1 - 15 mg/l) is linked to the low incidence of heart diseases in some regions of France, the so-called ‘French paradox’ i.e., despite high fat intake, mortality from coronary heart disease is lower due to the regular drinking of wine. This compound has attracted considerable attention due to its various biological and pharmacological activities, including antioxidative and anticancer activities. As a part of our ongoing research project on antioxidative effects of natural antioxidants and their derivatives we found recently that some synthetic resveratrol analogues bearing ortho-dihydroxyl functionality exhibit significantly higher antioxidant and cytotoxic activity against HL-60 cancer cells than resveratrol and other analogues bearing no such functionality. Therefore, it is desirable to see if the same structure–activity relationship is also valid in LDL peroxidation. We report herein an in vitro study on the antioxidative effect of resveratrol and related trans-stilbene analogues on free-radical-induced LDL peroxidation. The compounds studied are resveratrol, 3,4,3’,4’-tetrahydroxy-trans-stilbene (3,4,3’,4’-THS), 3,4,40-trihydroxy-trans-stilbene (3,4,4’-THS), 2,4,4’-trihydroxy-trans-stilbene (2,4,4’-THS), 3,30-dimethoxy-4,40-dihydroxy-trans-stilbene (3,3’-DM-4,4’-DHS), 3,4-dihydroxy-trans-stilbene (3,4-DHS), 4,40-dihydroxy-trans-stilbene (4,4’-DHS), 3,5-dihydroxy- trans-stilbene (3,5-DHS) and 2,4-dihydroxy-trans-stilbene (2,4-DHS). The peroxidation was initiated by a water-soluble azo initiator 2,20-azobis(2-amidinopropane hydrochloride) (AAPH) and cupric ion (Cu2+), and measured by oxygen uptake and formation of thiobarbituric acid reactive substances (TBARS). It was found that resveratrol and its analogues, especially 3,4,3’,4’-THS, 3,4,4’-THS, 3,4-DHS, and 3,3’-DM-4,4’- DHS, are good antioxidants for both AAPH- and cupric ion-initiated LDL peroxidation.The structure–activity relationship is discussed.
Bioorganic Chemistry 34 (2006) 142–157
