Experimental and Computational Studies on Newly Synthesized Resveratrol Derivative: A New Method for Cancer Chemoprevention and Therapeutics? (original) (raw)
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Applied Biochemistry and Biotechnology, 2013
Resveratrol (RVS) is a naturally occurring antioxidant, able to display an array of biological activities. In the present investigation, a new derivative of RVS, RVS(a), was synthesized, and its biological activity was determined on U937 cells. It was observed that RVS(a) showed pronounced activity on U937 cells than RVS. RVS(a) is able to induce apoptosis in tumor cell lines through subsequent DNA fragmentation. From the EMSA results, it was evident that RVS(a) was able to suppress the activity of NFkB by interfering its DNA binding ability. Furthermore, the molecular interaction analysis (docking and dynamics) stated that RVS(a) has strong association with the IkB-alpha site of NFkB compared with RVS; this binding nature of RVS(a) might be prevent the NFkB binding ability with DNA. The present findings represent the potential activity of propynyl RVS on U937 cells and signifying it as a one of putative chemotherapeutic drugs against cancer.
Journal of Applied Biomedicine, 2020
Resveratrol (RESV), an anticancer nutraceutical compound, is known to show poor bioavailability inside the human body. Therefore, this study has designed multiple chemical analogs of RESV compound for improving its pharmacokinetic as well as its anti-cancer properties. Initially, the drug likeliness and ADME-toxicity properties of these new chemical analogs were tested with the help of diverse computational approaches. Then the best predicted RESV derivative is synthesized by the organic method, and its NF-κB mediated anti-tumor activity assessed on histiocytic lymphoma U-937 cells. The new synthetic RESV analog, i.e. (E)-3-(prop-2-yn-1-yloxy)-5-(4-(prop-2-yn-1-yloxy) styryl) phenol has shown a rapid, persistent and better dose-dependent (IC 50 of 7.25 μM) decrease in the viability of U937 cells than the native (IC 50 of 30 μM) RESV compound. This analog has also demonstrated its potential ability in inducing apoptosis through DNA ladder formation. At 10 μg/ml concentration, this chemical derivative has shown a better NF-κB inhibition (IC 50 is 2.45) compared to the native RESV compound (IC 50 is 1.95). Molecular docking analysis found that this analog exerts its anti-NF-κB activity (binding energy of-6.78 kcal/mol and Ki 10 μM) by interacting with DNA binding residues (Arg 246 , Lys 444 , and Gln 606) of p50 chain NF-κB. This study presents a novel RESV analog that could further develop as a potential anti-NF-κB mediated tumor inhibitor.
Synthesis and evaluation of resveratrol derivatives as new chemical entities for cancer
Journal of Molecular Graphics and Modelling, 2013
Resveratrol has been shown to be active in inhibiting multistage carcinogenesis. The potential use of resveratrol in cancer chemoprevention or chemotherapy settings has been hindered by its short halflife and low bioavailability. Considering the above remarks, using resveratrol as a prototype, we have synthesized two derivatives of resveratrol. Their activity was evaluated using in vitro and in silico analysis. Biological evaluation of resveratrol analogues on U937 cells had shown that two synthesized analogues of resveratrol had higher rates of inhibition than the parental molecule at 10 M concentration. EMSA conducted for NF-kB revealed that these molecules significantly interfered in the DNA binding ability of NF-kB. It was found that these molecules suppressed the expression of TNF␣, TNFR, IL-8, actin and activated the expression of FasL, FasR genes. To understand possible molecular mechanism of the action we performed docking and dynamic studies, using NF-kB as a receptor. Results showed that resveratrol, RA1 and RA2 interacted with the residues involved in DNA binding. Resveratrol analogues by interacting NF-kB might have prevented its translocation and also by interacting with the residues involved in DNA binding might have prevented the binding of NF-kB to DNA. This may be the reason for suppression of NF-kB binding to DNA.
Resveratrol: Biological and pharmaceutical properties as anticancer molecule
Biofactors, 2010
There is ample evidence that shows an inverse relationship between consumption of fruit/vegetable-rich diets and the risk of cancer at various anatomical sites. In this review, we will assess and summarize recent advances on cancer prevention by resveratrol, a natural stilbenoid present in red grapes, peanuts, some common drinks, and dietary supplements. We will focus on data published within the past few years on in vivo model tumor animal studies that reinforce the chemopreventive efficacy of resveratrol against a multitude of cancers, as well as on its sensitization/ enhancing activities against tumor cells when used in combination with established chemotherapeutic and pharmaceutical agents. In addition, we will review examples resveratrol-target proteins, denoted RTPs, including the 24-kDa cytosolic protein quinone reductase 2 (NQO2) discovered in our laboratory that may confer resveratrol responsiveness to cancer cells. We will discuss the possible role of NQO2 in mediating cancer prevention by resveratrol. Our analysis of published data strengthen support that resveratrol displays novel roles in various cellular processes, and help to establish an expanded molecular framework for cancer prevention by resveratrol in vivo.
Multiple molecular targets of resveratrol: Anti-carcinogenic mechanisms
Archives of Biochemistry and Biophysics, 2009
Plant-derived polyphenolic compounds, such as the stilbene resveratrol (trans-3, 4', 5trihydroxystilbene), have been identified as potent anti-cancer agents. Extensive in vitro studies revealed multiple intracellular targets of resveratrol, which affect cell growth, inflammation, apoptosis, angiogenesis, and invasion and metastasis. These include tumor suppressors p53 and Rb; cell cycle regulators, cyclins, CDKs, p21WAF1, p27KIP and INK and the checkpoint kinases ATM/ ATR; transcription factors NF-κB, AP-1, c-Jun, and c-Fos; angiogenic and metastatic factors, VEGF and matrix metalloprotease 2/9; cyclooxygenases for inflammation; and apoptotic and survival regulators, Bax, Bak, PUMA, Noxa, TRAIL, APAF, survivin, Akt, Bcl-2 and Bcl-X L. In addition to its well-documented anti-oxidant properties, there is increasing evidence that resveratrol exhibits pro-oxidant activity under certain experimental conditions, causing oxidative DNA damage that may lead to cell cycle arrest or apoptosis. This review summarizes in vitro mechanistic data available for resveratrol and discusses new potential anti-cancer targets and the anti-proliferative mechanisms of resveratrol.
Resveratrol as a chemopreventive agent: a promising molecule for fighting cancer
Current drug targets, 2006
Resveratrol (3,4',5 tri-hydroxystilbene) is a phytoalexin produced in hudge amount in grapevine skin in response to infection by Bothrytis cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Moreover, several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits such as prevention of vaso-coronary diseases and cancer. Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathw...
Biomolecules
Resveratrol, the most widely studied natural phytochemical, has been shown to interact with different target proteins. Previous studies show that resveratrol binds and inhibits DNA polymerases and some other enzymes; however, the binding and functioning mechanisms remain unknown. The elucidated knowledge of inhibitory mechanisms of resveratrol will assist us in new drug discovery. We utilized molecular docking and molecular dynamics (MD) simulation to reveal how resveratrol and structurally similar compounds bind to various nucleotide-dependent enzymes, specifically, DNA polymerases, HIV-1 reverse transcriptase, and ribonucleotide reductase. The results show that resveratrol and its analogs exert their inhibitory effects by competing with the substrate dNTPs in these enzymes and blocking elongation of chain polymerization. In addition, the results imply that resveratrol binds to a variety of other ATP-/NTP-binding proteins.
Blood
Resveratrol, a constituent of grapes and other food products, has been shown to prevent carcinogenesis in murine models. We report here that resveratrol induces apoptotic cell death in HL60 human leukemia cell line. Resveratrol-treated tumor cells exhibit a dose-dependent increase in externalization of inner membrane phosphatidylserine and in cellular content of subdiploid DNA, indicating loss of membrane phospholipid asymmetry and DNA fragmentation. Resveratrol-induced cell death is mediated by intracellular caspases as observed by the dose-dependent increase in proteolytic cleavage of caspase substrate poly (ADP-ribose) polymerase (PARP) and the ability of caspase inhibitors to block resveratrol cytotoxicity. We also show that resveratrol treatment enhances CD95L expression on HL60 cells, as well as T47D breast carcinoma cells, and that resveratrol-mediated cell death is specifically CD95-signaling dependent. On the contrary, resveratrol treatment of normal human peripheral blood ...
Structureactivity relationships of resveratrol and derivatives in breast cancer cells
… nutrition & food …, 2009
Resveratrol (RSV) is classified as a phytoestrogen due to its ability to interact with estrogen receptors (ERs). We assessed structure -activity relationships of RSV and the analogs 4,49-dihydroxystilbene (4,49-DHS), 3,5-dihydroxystilbene (3,5-DHS), 3,49-dihydroxystilbene (3,49-DHS), 4-hydroxystilbene (4-HS) using as model systems the ERa-positive and negative MCF7 and SkBr3 breast cancer cells, respectively. In binding assays and transfection experiments RSV and the analogs showed the following order of agonism for ERa: 3,49-DHS A 4,49-DHS A 4-HS A RSV, while 3,5-DHS did not elicit any ligand properties. Computational docking analysis and real-time PCR revealed for each analog a distinct ERa binding orientation and estrogen target gene expression profile. Interestingly, the aforementioned order of ligand activity was confirmed in proliferation assays which also showed the lack of growth stimulation by 3,5-DHS. Our data suggest that subtle changes in the structure of the RSV derivatives examined may be responsible for the different ERa-mediated biological responses observed in estrogen-sensitive cancer cells.