Design, Syntheses And Biological Evaluation Of Resveratrol Dimers And Their Derivatives

Resveratrol (3,5,4’-trihydroxy-trans-stilbene) is a natural polyphenol stilbene found in grapes and certain plants used as medicines. It is a phytoalexin which is produced in plants in response to external stimuli. Resveratrol has been reported to have a diverse range of pharmacological properties, including anti inflammatory, antiplatelet and antioxidant activities. It has been shown to be an estrogen receptor agonist and exerts effects on cell signaling pathways involved in tumor growth, cell proliferation and survival. Resveratrol can be biotransformed by Botrytis cinerea, a fungal grapevine pathogen, into resveratrol oligomers. In recent years, researchers have found that these oligomers also show a variety of biological activities. Some of these derivatives demonstrate more potent biological activities than resveratrol due to their polyphenol motifs. After years of research in our lab found that the resveratrol-pallidol have a weak estrogen-like and anti-estrogenic effects. However, due to the scarcity of resveratrol oligomers from natural sources, the demand of the research and clinical application couldn’t be met only through the extraction from natural plants.Therefore, four parts of works had been finished as below:1. A concise total syntheses of isopaucifloral F, Quadrangularin A and Pallidol, starting from commercially available3,5-dimethoxybenzoic acid, have been achieved by a sequential process. The overall synthetic strategy involves Nazarov cyclization, Ramberg-Backlund olefination, and Friedel-Crafts alkylation.2. Based on the analysis of the structure-activity relationship of resveratrol and computer-aided design, we found that the hydroxyl groups on the phenyl rings of resveratrol analogues may play an important role in their biological activity. Therefore, we manipulated the numbers and substituent patterns of hydroxyl groups, carbonyl groups of indenones, and olefinic bonds of indene moieties to explore the structure activity relationships. Fifty-eight novel derivatives of resveratrol dimers were designed and synthesized. For ease of discussion, we divided these compounds into four types of structures:indenone-type, indene-type, octahydropentalene-type and Sulfur-indene types. The anti-osteoporosis experiment of ovariectomized female rats in vivo showed that the natural products isopaucifloral F (4) can improve the symptoms of osteoporosis in ovariectomized female rats in a dose-dependent and time-dependent manner.3. We selected representative compounds into biological evaluation such as neuroprotection, anti-inflammatory effects anti-osteoporosis effect:(1) The compounds in indene-type, octahydropentalene-type exhibited good activities in vitro against paraquat-induced apoptosis in SH-SY5Y cells. Analogue25showed a potent neuroprotective effect at a low concentration (10μM). Further investigation showed that compound25could attenuate,paraquat-induced nuclear morphological changes, significantly decrease paraquat-induced ROS (reactive oxygen species) generation in SH-SY5Y cells and elevate the expression of SOD (Superoxide Dismutase) and GPx (glutathione peroxidase) in a dose-dependent manner. Furthermore, analogue25could decrease Bax protein levels in a concentration-dependent manner and increase Bcl-2protein expression, which was accompanied by increasing chances of cell survival.(2) The derivatives in indenone-type exhibited good inhibitory activities in vitro on LPS-induced NO production in RAW264.7cells. Among analogues,22a showed a significant inhibitory activity (51%inhibition at10μM). Further study revealed that compound22a could suppress LPS-induced iNOS expression, NO production, and IL-1β release in a concentration-dependently manner. The mechanism of action (MOA) involved for its anti-inflammatory responses was through signaling pathways of p38MAPK and JNK1/2, but not ERK1/2.4. On the basis of SERMs’ structural formula and computer-aided design, we introduced on the N-containing side chain to the isopaucifloral F, in order to increase the hydrophobic binding between the compound and estrogen receptor β, thereby improving their anti-tumor activity.8novel derivatives were designed, synthesized and selected into Hela cells to investigate their anti-tumer activity.Above all, on the basis of the novel Selective Estrogen Receptor Modulators-resveratrol dimers and their derivatives, a lot of creative and hard work has been done, which would help to develop the novel selective estrogen receptor modulators.