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Oxidative stress and high levels of reactive oxygen species (ROS) are linked to various age-related diseases and chronic conditions, including damage to oral tissues. Dexamethasone (DEX), a widely used glucocorticoid in dentistry, can have side effects like increased ROS production and delayed wound healing. Resveratrol (RSV) is known for its antioxidant properties, but its limited bioavailability hinders its clinical use. This study investigated the potential of two RSV derivatives ( 1d and 1h ) to address these limitations. The antioxidant abilities of 1d and 1h (5 μM) against DEX-induced oxidative stress (200 μM) were evaluated in human gingival fibroblasts (hGFs) and osteoblasts (hOBs). The effects of these compounds on cell viability, morphology, ROS levels, SOD activity, gene expression, and collagen production were evaluated. RSV derivatives, under DEX-induced oxidative stress condition, improved cell growth at 72 h (191.70 ± 10.92% for 1d +DEX and 184.80 ± 13.87% for 1h +DEX), morphology, and SOD activity (77.33 ± 3.35 OD for 1d +DEX; 76.87 ± 3.59 OD for 1h +DEX at 1 h), while reducing ROS levels (2417.33 ± 345.49 RFU for 1d +DEX and 1843.00 ± 98.53 RFU at 4 h), especially in hOBs. The co-treatment of RSV or derivatives with DEX restored the expression of genes that were downregulated by DEX, such as HO-1 (1.76 ± 0.05 for 1d +DEX and 1.79 ± 0.01 for 1h +DEX), CAT (0.97 ± 0.06 for 1d +DEX and 0.99 ± 0.03 for 1h +DEX), NRF2 (1.62 ± 0.04 for 1d +DEX and 1.91 ± 0.05 for 1h +DEX), SOD1 (1.63 ± 0.15 for 1d +DEX and 1.69 ± 0.04 for 1h +DEX). In addition, 1d and 1h preserved collagen production (111.79 ± 1.56 for 1d +DEX and 122.27 ± 1.56 for 1h +DEX). In conclusion, this study suggests that the RSV derivatives 1d and 1h hold promise as potential antioxidant agents to counteract DEX-induced oxidative stress. These findings contribute to the development of novel therapeutic strategies for managing oxidative stress-related oral conditions.

Colorectal cancer is the second leading cause of cancer-related deaths. In 2018, there were an estimated 1.8 million cases, and this number is expected to increase to 2.2 million by 2030. Despite its prevalence, the current therapeutic option has a lot of side effects and limitations. Therefore, this study was designed to employ a computational approach for the identification of anti-cancer inhibitors against colorectal cancer using Resveratrol derivatives. Initially, the pass prediction spectrum of 50 derivatives was conducted and selected top seven compounds based on the maximum pass prediction score. After that, a comprehensive analysis, including Lipinski Rule, pharmacokinetics, ADMET profile study, molecular orbitals analysis, molecular docking, molecular dynamic simulations, and MM-PBSA binding free energy calculations. The reported binding affinity ranges of Resveratrol derivatives from molecular docking were -6.1 kcal/mol to -7.9 kcal/mol against the targeted receptor of human armadillo repeats domain of adenomatous polyposis coli (APC) (PDB ID: 3NMW). Specifically, our findings reported that two compounds [(03) Resveratrol 3-beta-mono-D-glucoside, and (29) Resveratrol 3-Glucoside] displayed the highest level of effectiveness compared to all other derivatives (-7.7 kcal/mol and -7.9 kcal/mol), and favorable drug-likeness, and exceptional safety profiles. Importantly, almost all the molecules were reported as free from toxic effects. Subsequently, molecular dynamic simulations conducted over 100ns confirmed the stability of the top two ligand-protein complexes. These findings suggest that Resveratrol derivatives may be effective drug candidate to manage the colorectal cancer. However, further experimental research, such as in vitro / in vivo studies, is essential to validate these computational findings and confirm their practical value., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Akash, Islam, Bhuiyan, Islam, Bayıl, Saleem, Albadrani, Al-Ghadi and Abdel-Daim.)

Resveratrol and its derivatives are the most important phytoalexins with a crucial role in plant defense mechanisms. These compounds can occur either naturally or in response to abiotic stresses. Among them, salinity is one of the major threats to the sustainability and productivity of agro-economically important species, particularly those involved in the vini-viticulture sector. Understating salinity tolerance mechanisms in plants is required for the development of novel engineering tools. This study aimed to investigate the potential role of resveratrol derivatives in salinity tolerance of wild grapevines. Our data revealed that the tolerant Tunisian wild grapevine genotype "Ouchtata" exhibited an increased accumulation of resveratrol derivatives (glycosylated and non-glycosylated resveratrol and t-ɛ-viniferin and hydroxylated t-piceatannol) in both stems and roots, along with an increased total antioxidant activity (TAA) compared to the sensitive genotype "Djebba" under stress conditions, suggesting an involvement of these stilbenes in redox homeostasis, thereby, protecting cells from salt-induced oxidative damage. Overall, our study revealed, for the first time, an active role for resveratrol derivatives in salt stress tolerance in wild grapevine, highlighting their potential use as metabolic markers in future grapevine breeding programs for a sustainable vini-viticulture in salt-affected regions., (© 2023. The Author(s) under exclusive licence to The Botanical Society of Japan.)

Background: Resveratrol is a polyphenol that is found in plants and has been proposed to have a potential therapeutic effect through the activation of SIRT1, which is a crucial member of the mammalian NAD+ -dependent deacetylases. However, how its activity is enhanced toward specific substrates by resveratrol derivatives has not been studied. This study aimed to evaluate the types of interaction of resveratrol and its derivatives with SIRT1 as the target protein, as well as to find out the best ligand with the strangest interaction with SIRT1., Materials and Methods: In this study, we employed the extensive molecular docking analysis using AutoDock Vina to comparatively evaluate the interactions of resveratrol derivatives (22 molecules from the ZINC database) as ligands with SIRT1 (PDB ID: 5BTR) as a receptor. The ChemDraw and Chem3D tools were used to prepare 3D structures of all ligands and energetically minimize them by the MM2 force field., Results: The molecular docking and visualizations showed that conformational change in resveratrol derivatives significantly influenced the parameter for docking results. Several types of interactions, including conventional hydrogen bonds, carbon-hydrogen bonds, Pi-donor hydrogen bonds, and Pi-Alkyl, were found via docking analysis of resveratrol derivatives and SIRT1 receptors. The possible activation effect of resveratrol 4'-(6-galloylglucoside) with ZINC ID: ZINC230079516 with higher binding energy score (-46.8608 kJ/mol) to the catalytic domain (CD) of SIRT1 was achieved at the maximum value for SIRT1, as compared to resveratrol and its other derivatives., Conclusion: Finally, resveratrol 4'-(6-galloylglucoside), as a derivative for resveratrol, has stably interacted with the CD of SIRT1 and might be a potential effective activator for SIRT1., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

With the intensification of population aging, aging-related diseases are attracting more and more attention, thus, the study of aging mechanisms and anti-aging drugs is becoming increasingly urgent. Resveratrol is a potential candidate as an anti-aging agent, but its low bioavailability limits its application in vivo. In this work, a 4-hydroxy-3'-trifluoromethoxy-substituted resveratrol derivative ( 4-6 ), owing to its superior cell accumulation, could inhibit NO production in an inflammatory cell model, inhibit oxidative cytotoxicity, and reduce ROS accumulation and the population of apoptotic cells in an oxidative stress cell model. In D-galactose (D-gal)-stimulated aging mice, 4-6 could reverse liver and kidney damage; protect the serum, brain, and liver against oxidative stress; and increase the body's immunity in the spleen. Further D-gal-induced brain aging studies showed that 4-6 could improve the pathological changes in the hippocampus and the dysfunction of the cholinergic system. Moreover, protein expression related to aging, oxidative stress, and apoptosis in the brain tissue homogenate measured via Western blotting also showed that 4-6 could ameliorate brain aging by protecting against oxidative stress and reducing apoptosis. This work revealed that meta -trifluoromethoxy substituted 4-6 deserved to be further investigated as an effective anti-aging candidate drug.

Besides the use of resveratrol as a drug candidate, there are obstacles mainly due to its poor pharmacokinetic properties. Numerous studies are being conducted on the synthesis of resveratrol derivatives that exhibit enhanced biological activity. The aim of our research was to investigate activity of the newly synthesized ferrocene-containing triacyl derivative of resveratrol to achieve cell protection from endo/exogenous ROS and reduction in cell death by assessing multiple endpoints. Our research showed that both resveratrol and the resveratrol derivatives (1-100 μM) lower the levels of ROS in CHO-K1 cells. Resveratrol at doses <20 μM had little or no effect on cell proliferation, while at higher doses, a significant inhibitory effect on cell proliferation and viability has been noticed. The activity of the new derivative was significantly altered compared to resveratrol-cellular viability was not suppressed regardless of the concentration applied, and the extent of apoptosis was low. In summary, the new ferrocene-resveratrol derivative has the potential to protect cells from oxidative stress due to its low cytotoxicity and retained antioxidant properties, whereas caution should be exercised with resveratrol at higher doses, as it significantly impairs cell viability and induces cell death. By linking ROS to specific diseases (relevance in neurodegenerative, cardiovascular, and neoplastic diseases), we can assume that the new resveratrol derivative can prevent or alleviate the mentioned disorders. Furthermore, recognition of the resveratrol derivative as an anti-apoptotic chemical could be useful in the cultivation of various cell lines on a large scale in the industrial biotechnology., (© 2023 John Wiley & Sons Ltd.)

Recently, there has been an increasing interest in finding new approaches to manage oral wound healing. Although resveratrol (RSV) exhibited many biological properties, such as antioxidant and anti-inflammatory activities, its use as a drug is limited by unfavorable bioavailability. This study aimed to investigate a series of RSV derivatives ( 1a - j ) with better pharmacokinetic profiles. At first, their cytocompatibility at different concentrations was tested on gingival fibroblasts (HGFs). Among them, derivatives 1d and 1h significantly increased cell viability compared to the reference compound RSV. Thus, 1d and 1h were investigated for cytotoxicity, proliferation, and gene expression in HGFs, endothelial cells (HUVECs), and oral osteoblasts (HOBs), which are the main cells involved in oral wound healing. For HUVECs and HGFs, the morphology was also evaluated, while for HOBs ALP and mineralization were observed. The results showed that both 1d and 1h did not exert negative effects on cell viability, and at a lower concentration (5 µM) both even significantly enhanced the proliferative rate, compared to RSV. The morphology observations pointed out that the density of HUVECs and HGFs was promoted by 1d and 1h (5 µM) and mineralization was promoted in HOBs. Moreover, 1d and 1h (5 µM) induced a higher eNOS mRNA level in HUVECs, higher COL1 mRNA in HGFs, and higher OCN in HOBs, compared to RSV. The appreciable physicochemical properties and good enzymatic and chemical stability of 1d and 1h , along with their promising biological properties, provide the scientific basis for further studies leading to the development of RSV-based agents useful in oral tissue repair.

The Akt-mTOR signal is important for the survival and proliferation of cancer cells and has become an interesting drug target. In this study, five resveratrol derivatives were evaluated for anticancer activity and Akt/mTOR targeting activity in non-small lung cancer cell lines. The effects of resveratrol derivatives on cell proliferation were assessed by 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, nucleus staining, and colony formation assay. Furthermore, the effect of resveratrol derivatives on proliferation-related protein expression was analyzed by immunofluorescence and Western blotting. For the structure-activity relationship (SAR), results reveal that two derivatives of resveratrol which are 4,4'-(ethane-1,2-diyl) bis(2-methoxyphenol) (RD2) and the 4-(3-hydroxy-4-methoxyphenethyl)-2-methoxyphenol (RD3) had very similar structures but exerted different cytotoxicity. The IC 50 of RD2 and RD3 were 108.6 ± 10.82 and more than 200 µM in the A549 cell line and 103.5 ± 6.08 and more than 200 µM in H23 cells, respectively. RD2 inhibited cell proliferation and induced apoptosis when compared with the control, while RD3 caused minimal effects. Cells treated with RD2 exhibited apoptotic nuclei in a concomitant with the reduction of cellular p -Akt and p -mTOR. RD3 had minimal effects on such proteins. According to these results, molecular docking analysis revealed a high-affinity interaction between RD2 and an Akt molecule at the ATP-binding and the allosteric sites, indicating this RD2 as a potential Akt inhibitor. This study provides useful information of resveratrol derivatives RD2 for treating lung cancer via Akt/mTOR inhibition.

A phytoalexin, Resveratrol remains a legendary anticancer drug candidate in the archives of scientific literature. Although earlier wet-lab experiments rendering its multiple biological targets, for example, epidermal growth factors, Pro-apoptotic protein p53, sirtuins, and first apoptosis signal (Fas) receptor, Mouse double minute 2 (MDM2) ubiquitin-protein ligase, Estrogen receptor, Quinone reductase, etc. However, notwithstanding some notable successes, identification of an appropriate Resveratrol target(s) has remained a major challenge using physical methods, and hereby limiting its translation into an effective therapeutic(s). Thus, computational insights are much needed to establish proof-of-concept towards potential Resveratrol target(s) with minimum error rate, narrow down the search space, and to assess a more accurate Resveratrol signaling pathway/mechanism at the starting point. Herein, a brute-force technique combining computational receptor-, ligand-based virtual screening, and classification-based machine learning, reveals the precise mechanism of Resveratrol action. Overall, MDM2 ubiquitin-protein ligase (4OGN.pdb) and co-crystallized quinone reductases 2 (4QOH.pdb) were found two suitable drug targets in the case of Resveratrol derivatives. Indeed, carotenoid cleaving oxygenase together with later twos gave gigantic momentum in guiding the rational drug design of Resveratrol derivatives. These molecular modeling insights would be useful for Resveratrol lead optimization into a more precise science.Communicated by Ramaswamy H. Sarma.

Background: Overexpression of LSD1 is associated with the occurrence of many diseases, including cancers, which makes LSD1 a significant target for anticancer drug research. Methodology & Results: With the aid of 3D quantitative structure-activity relationship models established with 34 reported resveratrol derivative LSD1 inhibitors, derivatives 35 - 40 were designed. Absorption, distribution, metabolism and excretion calculations showed that they may have good bioavailability and drug likeness. Additionally, 35 and 37 presented good antitumor effects in an in vitro antiproliferative assay. Molecular docking and molecular dynamics simulation results indicated that 35 and 37 can establish extensive interactions with LSD1. Conclusion: The results of computational prediction and experimental validation suggest that 35 and 37 are effective antitumor inhibitors, which provides some ideas and directions for the development of new anticancer LSD1 inhibitors.

Viruses continue to be a major threat to human health. In the last century, pandemics occurred and resulted in significant mortality and morbidity. Natural products have been largely screened as source of inspiration for new antiviral agents. Within the huge class of plant secondary metabolites, resveratrol-derived stilbenoids present a wide structural diversity and mediate a great number of biological responses relevant for human health. However, whilst the antiviral activity of resveratrol has been extensively studied, little is known about the efficacy of its monomeric and oligomeric derivatives. The purpose of this review is to provide an overview of the achievements in this field, with particular emphasis on the source, chemical structures and the mechanism of action of resveratrol-derived stilbenoids against the most challenging viruses. The collected results highlight the therapeutic versatility of stilbene-containing compounds and provide a prospective insight into their potential development as antiviral agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Resveratrol is a natural phytoestrogen produced by plants to protect themselves from injury, UV irradiation, and fungal attack. The main active structure is E-resveratrol, which has many pharmacological activities. As the structure of resveratrol is similar to the natural estrogen 17β-estradiol and the synthetic estrogen E-diethylstilbestrol, resveratrol is used in reducing the incidence of breast cancer. However, the therapeutic application of resveratrol is limited due to its low bioavailability. To improve its bioavailability and pharmacological activity, some resveratrol derivatives have been designed and synthesized by substitutions of methoxy, hydroxyl, and other functional groups or heterocyclic esterification either on the "A" or "B" ring, and double bonds were replaced by imine bonds and isometric heterocycles such as naphthyl and imidazole, or synthetic resveratrol oligomers. The structures, synthetic routes, and evaluation of the biological activities of these compounds are discussed. These are aimed at providing some references for the study of resveratrol derivatives in anti-breast cancer treatment., (© 2020 Deutsche Pharmazeutische Gesellschaft.)

The escalating emergence of resistant bacterial strains is one of the most important threats to human health. With the increasing incidence of multi-drugs infections, there is an urgent need to restock our antibiotic arsenal. Natural products are an invaluable source of inspiration in drug design and development. One of the most widely distributed groups of natural products in the plant kingdom is represented by stilbenoids. Stilbenoids are synthesised by plants as means of protection against pathogens, whereby the potential antimicrobial activity of this class of natural compounds has attracted great interest in the last years. The purpose of this review is to provide an overview of recent achievements in the study of stilbenoids as antimicrobial agents, with particular emphasis on the sources, chemical structures, and the mechanism of action of the most promising natural compounds. Attention has been paid to the main structure modifications on the stilbenoid core that have expanded the antimicrobial activity with respect to the parent natural compounds, opening the possibility of their further development. The collected results highlight the therapeutic versatility of natural and synthetic resveratrol derivatives and provide a prospective insight into their potential development as antimicrobial agents.

Resveratrol (3,5,4'-trihydroxystilbene; RSV) is a natural nonflavonoid polyphenol present in many species of plants, particularly in grapes, blueberries, and peanuts. Several in vitro and in vivo studies have shown that in addition to antioxidant, anti-inflammatory, cardioprotective and neuroprotective actions, it exhibits antitumor properties. In mammalian models, RSV is extensively metabolized and rapidly eliminated and therefore it shows a poor bioavailability, in spite it of its lipophilic nature. During the past decade, in order to improve RSV low aqueous solubility, absorption, membrane transport, and its poor bioavailability, various methodological approaches and different synthetic derivatives have been developed. In this review, we will describe the strategies used to improve pharmacokinetic characteristics and then beneficial effects of RSV. These methodological approaches include RSV nanoencapsulation in lipid nanocarriers or liposomes, nanoemulsions, micelles, insertion into polymeric particles, solid dispersions, and nanocrystals. Moreover, the biological results obtained on several synthetic derivatives containing different substituents, such as methoxylic, hydroxylic groups, or halogens on the RSV aromatic rings, will be described. Results reported in the literature are encouraging but require additional in vivo studies, to support clinical applications.

Resveratrol, also known as 3,5,4'-trihydroxystilbene, is a natural polyphenol that occurs as a phytoalexin. It is produced by plant sources such as grapes, apples, blueberries, plums, peanuts, and other oilseeds. This compound has a variety of effects on human health and diseases. This review summarizes the mounting evidence that resveratrol is helpful in treating metabolic syndrome and related disorders. Resveratrol can be provided either early as a reprogramming agent or later as part of treatment. A few of the main mechanisms underlying the beneficial effects of resveratrol on metabolic syndrome are outlined. This review also discusses the potential of resveratrol derivatives as a complementary or alternative medicine. In conclusion, resveratrol could be a useful regimen for the prevention and treatment of metabolic syndrome and its related conditions.

Introduction: Resveratrol has been reported to alleviate inflammatory responses and oxidative stress in mesangial cells and in several types of renal injury in animal models. Previously, the active resveratrol derivatives from the roots of Vitis thunbergii Sieb. & Zucc. (Vitaceae) were shown to have significant anti-platelet and anti-oxidative activities. However, the anti-inflammatory mechanisms of these resveratrol derivatives in rat mesangial cells (RMCs) have not been clarified fully., Methods: The protective mechanisms of resveratrol derivatives involved in tumor necrosis factor-α (TNF-α)-induced inflammatory responses were assessed by Western blot analysis, real-time PCR, and RT-PCR. The involvement of various signaling molecules in these responses was investigated using selective pharmacological inhibitors., Results: Nontoxic concentrations of the resveratrol derivatives significantly attenuated cytosolic phospholipase A 2 (cPLA 2 ) and cyclooxygenase 2 (COX-2) expression in RMCs challenged by TNF-α. These resveratrol derivatives inhibited TNF-α-activated ERK1/2 and JNK1/2 without affecting p38 phosphorylation. Next, we demonstrated that TNF-α induced NF-κB activation, translocation, and promoter activity, which was inhibited by pretreatment with resveratrol derivatives in RMCs., Conclusion: The protective mechanisms of resveratrol derivatives against TNF-α-stimulated inflammatory responses via cPLA 2 /COX-2/PGE 2 inhibition was caused by the attenuation of the JNK1/2, ERK1/2, and NF-κB signaling pathways in RMCs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Commiphora africana (A. Rich.) Endl. (Burseraceae) is a medicinal plant widely used in Nigerian ethnomedicine. The in vitro cytotoxicity of the stem bark extract of C. africana and isolated cytotoxic compounds was investigated. Three resveratrol derivatives: (E)-resveratrol 3-O-rutinoside (1), 5-methoxy-(E)-resveratrol 3-O-rutinoside (2), and pinostilbene (3), together with 3-hydroxy-5-methoxybenzoic acid (4) were isolated from the methanol fraction of C. africana. Their structures were determined by extensive analysis of their HREIMS and NMR spectra. The cytotoxicity of the isolated compounds against four human carcinoma cells was determined using the MTT assay. Compound 1 displayed the highest antiproliferative effect on the cell lines, with IC 50 values of 16.80, 21.74, 17.89, and 17.44 μM, against MCF7, A549, PC3, and HepG2 human cancer cell lines, respectively. In addition, compounds 1-3 showed low toxicity against normal human prostate cell line, with selectivity indices greater than five across the carcinoma cells, indicating that the compounds possess potential in the development of low-toxicity chemotherapeutic agents. These results support the traditional use of this plant in the treatment of cancer., (© 2018 John Wiley & Sons, Ltd.)

T rans -resveratrol, the most well-known polyphenolic stilbenoid, is found in grapes and accordingly in wine and it is considered to be beneficial for human health, especially towards the aging-linked cell alterations by providing numerous biological activities, such as anti-oxidant, antitumoral, antiviral, anti-inflammatory, neuroprotective, and platelet anti-aggregation properties. Although trans -resveratrol derivatives, with the aim to increase its solubility in water and pharmacological activities towards cell targets. The aim of this review is to show the chronological evolution over the last 25 years of different strategies to develop more efficient trans -resveratrol derivatives towards organism physiology and, therefore, to enhance various pharmacological activities. While the literature on the development of new synthetic derivatives is impressive, this review will focus on selected strategies regarding the substitution of trans -resveratrol derivatives towards organism physiology and, therefore, to enhance various pharmacological activities. While the literature on the development of new synthetic derivatives is impressive, this review will focus on selected strategies regarding the substitution of trans -resveratrol phenyl rings, first with hydroxy, methoxy, and halogen groups, and next with functionalized substituents. The effects on cell functions and dysfunctions of interesting resveratrol analogs will be addressed in this review., Competing Interests: The authors declare no conflict of interest.

Twenty-three novel resveratrol-based cinnamic ester hybrids were designed and synthesized. All the compounds were evaluated for their anti-inflammatory activity using RAW264.7 cells. Among them, compound D15 was found to be the most potent one in inhibiting NO production in LPS-stimulated RAW264.7 cells. The further study indicated that compound D15 could suppress expression of proteins iNOS, COX-2, p-p65, and p-IκB LPS-induced. Immunofluorescence further revealed compound D15 could reduce activation p65 in nuclei. All the results indicated that the anti-inflammatory activity of title compound may partly due to its inhibitory effect on the NF-κB signaling pathway.

Triple-negative breast cancer is a highly aggressive subtype of breast cancer. Frequently, breast cancer cells modulate their calcium signaling pathways to optimize growth. Unique calcium pathways in breast cancer cells could serve as a way to target tumorigenic cells without affecting normal tissue. Resveratrol has previously been shown to activate calcium signaling pathways. We use cell viability, single-cell calcium microscopy, and RT-PCR assays to determine the activity and mechanism of three different 4'-esterified resveratrol derivatives. We demonstrate that two of the derivatives reduce cell viability more effectively than resveratrol in MDA-MB-231 human breast cancer cells. The derivatives also activate similar pro-apoptotic calcium signaling pathways. In particular, the pivalated and butyrated resveratrol derivatives are intriguing putative chemotherapeutics because they are more effective at decreasing cell viability in vitro and inhibiting the plasma membrane Ca 2+ -ATPase, a protein that is often modulated in breast cancer., Competing Interests: The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Resveratrol, a natural phytoalexin, exhibits a remarkable range of biological activities, such as anticancer, cardioprotective, neuroprotective and antioxidant properties. However, the therapeutic application of resveratrol was encumbered for its low bioavailability. Therefore, many researchers focused on designing and synthesizing the derivatives of resveratrol to enhance the bioavailability and the pharmacological activity of resveratrol. During the past decades, a large number of natural and synthetic resveratrol derivatives were extensively studied, and the methoxylated, hydroxylated and halogenated derivatives of resveratrol received particular more attention for their beneficial bioactivity. So, in this review, we will summarize the chemical structure and the therapeutic versatility of resveratrol derivatives, and thus provide the related structure activity relationship reference for their practical applications., Competing Interests: The authors declare no conflict of interest.

A series of deferiprone-resveratrol hybrids have been designed and synthesized as multitarget-directed ligands (MTDLs) through merging the chelating moiety 3-hydroxypyridin-4-one into the structure of resveratrol, a natural antioxidant agent and β-amyloid peptide (Aβ) aggregation inhibitor. The in vitro biological evaluation revealed that most of these newly synthesized compounds exhibited good inhibitory activity against self-induced Aβ 1-42 aggregation, excellent antioxidant activity and potent metal chelating capability. Compounds 3i and 4f were identified as the most promising MTDLs with triple functions, possessing micromolar IC 50 values for Aβ 1-42 aggregation inhibition, greater 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS •+ ) scavenging activity than Trolox and similar pFe(III) values to that of deferiprone., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Inhibition of lysine-specific demethylase 1 (LSD1) has recently emerged as an attractive therapeutic target for treating cancer and other diseases. As a continuity of our ongoing effort to identify novel small-molecule LSD1-inhibitors, we designed and synthesized a series of resveratrol derivatives, which were shown to be potent inhibitors of LSD1. Among them, compounds 4e and 4m displayed the most potent LSD1-inhibitory activities in enzyme assays, with IC 50 values of 121 nM and 123 nM, respectively. Biochemistry study and docking analysis indicated that compounds 4e and 4m were reversible LSD1 inhibitors. High content analysis showed that 4e and 4m induced a dose-dependent increase of dimethylated Lys4 of histone H3 and had no impact on the expression of LSD1 in MGC-803 cells. Furthermore, 4e or 4m could remarkably increase the mRNA level of CD86, a surrogate cellular biomarker for LSD1 activity, in MGC-803 cells, suggesting that they are likely to exhibit LSD1-inhibitory activities intracellularly. These findings should encourage further modification of these compounds to produce more potent LSD1 inhibitors with potential anticancer activity., (Copyright © 2016 Elsevier Masson SAS. All rights reserved.)

Introduction: Resveratrol is a well-studied natural small molecule that possesses diverse bioactivities. Chemical derivation based on the resveratrol scaffold is of great importance to overcome the drawbacks of resveratrol and to improve its therapeutic potential. Continuous efforts have been established to develop resveratrol derivatives that target different therapeutic applications. Areas covered: This review covers patents published from 2012 to 2015. All resveratrol derivatives discussed are classified based on its derivation strategy as simple derivatives, conjugated derivatives and miscellaneous derivatives. Their therapeutic related activities are reviewed and discussed. Expert opinion: Chemical derivation is an effective strategy to enhance the benefits of resveratrol and ameliorate its disadvantages. Recent studies on resveratrol derivatives have made great progress in the treatment of cancer and neurodegenerative diseases to name a few, demonstrating improved activity compared with resveratrol. Notably, its bioavailability was also improved in some cases. However, the 'next generation' of resveratrol derivatives still requires the development of new strategies and techniques.

In the title mol-ecule, C19H20O4, the central C=C double bond adopts an E configuration. The dihedral angle formed by the planes of the two benzene rings is 83.57 (12)°. The three meth-oxy groups are essentially coplanar with the benzene rings to which they are attached, with C C-O-C torsion angles of -0.2 (3), -2.3 (3) and -4.1 (3)°.

Resveratrol (1), a naturally occurring stilbene compound, has been suggested as a potential whitening agent with strong inhibitory activity on melanin synthesis. However, the use of resveratrol in cosmetics has been limited due to its chemical instability and poor bioavailability. Therefore, resveratrol derivatives were prepared to improve bioavailability and anti-melanogenesis activity. Nine resveratrol derivatives including five alkyl ether derivatives with C₂H₅, C₄H₉, C₅H11, C₆H13, and C₈H17 (2a-2e) and four ester derivatives with CH₃, CH=C(CH₃)₂, CH(C₂H₅)C₄H₉, C₇H15 (3a-3d) were newly synthesized and their effect on melanin synthesis were assessed. All the synthetic derivatives efficiently reduced the melanin content in α-MSH stimulated B16F10 melanoma cells. Further investigation showed that the inhibitory effect of 2a on melanin synthesis was achieved not by the inhibition of tyrosinase activity but by the inhibition of melanogenic enzyme expressions such as tyrosinase and tyrosinase-related protein (TRP)-1. Our synthetic resveratrol derivatives have more lipophilic properties than resveratrol by the addition of alkyl or acyl chains to free hydroxyl moiety of resveratrol; thus, they are expected to show better bioavailability in skin application. Therefore, we suggest that our synthetic resveratrol derivatives might be promising candidates for better practical application to skin-whitening cosmetics.

Melinjo (Gnetum gnemon L.) seed extracts (MSEs) are rich in resveratrol dimers (gnemonoside A, C, D, gnetin C), trans-resveratrol, and other resveratrol derivatives. trans-Resveratrol is a widely studied caloric restriction mimetic. In mice fed a high-fat diet (HFD), trans-resveratrol protects against obesity, type 2 diabetes, and premature death. Here, treatment of HFD-fed mice with 2.0% MSE significantly reduced body weight gain (p < 0.001), blood insulin (p < 0.01), and HOMA-IR (p < 0.05) after 8 weeks compared with untreated HFD-fed mice. Additionally, 0.2% MSE treatment of HFD-fed mice significantly improved physiological activity (p < 0.05) at 18 months of age and reduced risk of death due to HFD by 25% (hazard ratio = 0.75, p = 0.036). These data show that MSE can improve several aspects of metabolic syndrome and survival in mice and may have health benefits as a dietary supplement.

A series of imine resveratrol derivatives (1-20) have been designed, synthesized, and evaluated as multi-targeted compounds for the treatment of Alzheimer's disease (AD). In vitro studies show that most of the molecules exhibit a significant ability to inhibit self-induced and Cu(2+)-induced β-amyloid (Aβ₁₋₄₂) aggregation, and to function as potential antioxidants and biometal chelators. In particular, compound 9 is a potential lead compound for AD treatment (for compound 9, IC₅₀ = 14.1 μM for the antioxidant activity using DPPH free radical method; 64.6% at 20 μM for self-induced Aβ aggregation). Moreover, it is capable of decreasing reactive oxygen species (ROS) induced by Cu-Aβ and shows good neuroprotective effects in human SH-SY5Y neuroblastoma cells. Taken together, these results suggest that 9 might be a promising lead compound for AD treatment., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)

Chemical derivatization of resveratrol has been widely conducted in an effort to overcome its chemical instability and therapeutic potential. In the present study, we examined the anti-inflammatory effects of resveratrol derivatives containing an amide functionality using in vitro macrophage models that were stimulated by Toll-like receptor (TLR) ligands, and using several animal inflammatory disease models. Of the resveratrol derivatives tested, compound 8 (2,4-dihydroxy-N-(4-hydroxyphenyl)benzamide) most strongly inhibited the production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and prostaglandin E2 (PGE2), as well as the mRNA expression of inducible NO synthase (iNOS), TNF-α, and cyclooxygenase (COX)-2 in lipopolysaccharide (LPS)-activated RAW264.7 cells, differentiated U937 cells, and peritoneal macrophages. The inhibitory activity of compound 8 was apparently mediated by suppressing the phosphorylation of signal transducer and activator of transcription (STAT)-1, STAT-3, STAT-5, and interferon regulatory factor (IRF)-3. The direct target of compound 8 was revealed to be Janus kinase 2 (JAK2) but not TANK-binding kinase (TBK) 1 using the direct kinase assay and analyses of complex formation with these molecules. Additionally, upstream kinase of TBK1 seems to be also inhibited by compound 8. This compound also strongly ameliorated mouse inflammatory symptoms seen in arachidonic acid-induced ear edema, dextran sodium sulfate (DSS)-treated colitis, EtOH/HCl-induced gastritis, collagen type II-triggered arthritis, and acetic acid-induced writhing. Therefore, of the resveratrol derivatives that we tested, compound 8 was determined to have the strongest anti-inflammatory activities in vitro and in vivo and may potentially be developed for use as a novel anti-inflammatory drug., (Copyright © 2013 Elsevier Inc. All rights reserved.)