Stilbene Derivatives Research Articles

Evaluation of Anti-cancer Activity of Stilbene and Methoxydibenzo[b,f] oxepin Derivatives.

Stilbenes, 1,2-diphenylethen derivatives, including resveratrol and combretastatins, show anticancer features especially against tumor angiogenesis. Fosbretabulin, CA-4, in combination with carboplatin, is in the last stages of clinical tests as an inhibitor of thyroid cancer. The mode of action of these compounds involves suppression of angiogenesis through interfering with tubulin (de)polymerization. We have previously synthesized five E-2-hydroxystilbenes and seven dibenzo [b,f]oxepins in Z configuration, with methyl or nitro groups at varied positions. The aim of the present work was to evaluate the anticancer activity and molecular mechanism(s) of action of these compounds. Two healthy, EUFA30 and HEK293, and two cancerous, HeLa and U87, cell lines were treated with four newly synthetized stilbenes and seven oxepins. Two of these compounds, JJR5 and JJR6, showed the strongest cytotoxic effect against cancerous cells tested and these two were selected for further investigations. They induced apoptosis with sub-G1 or S cell cycle arrest and PARP cleavage, with no visible activation of caspases 3 and 7. Proteomic differential analysis of stilbene-treated cells led to the identification of proteins involved almost exclusively in cell cycle management, apoptosis, DNA repair and stress response, e.g. oxidative stress. Among the newly synthesized stilbene derivatives, we selected two as potent anticancer compounds triggering late apoptosis/necrosis in cancerous cells through sub-G1 phase cell cycle arrest. They changed cyclin expression, induced DNA repair mechanisms, enzymes involved in apoptosis and oxidative stress response. Compounds JJR5 and JJR6 can be a base for structure modification(s) to obtain even more active derivatives.

Abstract 5857: Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway

Abstract Breast cancer is the most prevalent cancer among women worldwide, and is the second leading cause of cancer mortality among women. Triple-negative breast cancers (TNBCs; ER-/PR-/HER2-) are highly aggressive tumors with poor prognosis. Due to lack of these specific receptors, TNBCs cannot be treated with hormone therapies or anti-HER2 targeted therapies. Chemotherapy, combined with surgery and radiation therapy, is the primary strategy for treating TNBCs. Thus, discovery and evaluation of new alternative medications targeting triple-negative breast cancer is of tremendous importance for reducing breast cancer mortality. Isorhapontigenin (ISO), a new derivative of stilbene isolated from Chinese herb Gnetum Cleistostachyun, exhibits a strong inhibitory effect on human bladder cancers. However, its anticancer activity with respect to breast cancer remains unclear. In the present study, we investigated the potential anticancer effect of ISO on TNBCs. ISO treatment inhibited the proliferation and anchorage-independent growth of 4T1 cells, a murine triple-negative breast cancer cell line, in a dose-dependent manner. In addition, the results from wound healing and Transwell invasion assay indicated significantly reduced cell migration and invasion in ISO-treated cells. Moreover, we performed the whole transcriptome analysis using RNA-seq to elucidate the molecules and pathways that mediate ISO's anticancer activity. A total of 1972 differentially expressed genes were identified in ISO-treated cells. IPA analysis revealed that the top canonical pathway altered by ISO is NRF2-mediated pathway. ISO-induced NRF2 activation was further confirmed by nuclear translocation of NRF2 protein and upregulation of NRF2 downstream target genes (GSTA1, GSTM1, HMOX1, and NQO1). In summary, our study is the first to demonstrate that ISO inhibits breast cancer cell growth and invasion, in part, by activating NRF2-mediated signaling pathway. Our results provide a novel mechanism for ISO-induced anticancer effect, and strongly support ISO as a promising therapeutic agent for triple-negative breast cancers. Citation Format: Yusha Zhu, Anthony Murphy, Thomas Kluz, Bo Li, Max Costa, Chuanshu Huang, Hong Sun. Isorhapontigenin inhibits triple-negative breast cancer via activating NRF2-mediated pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5857.

3D energy frameworks of a potential nutraceutical

A new stilbene derivative (potential neutraceutical), 1,3-dimethoxy-5-(4-((4-nitrobenzyl)oxy)styryl)benzene (STL) was synthesized, characterized by spectroscopy (1H, 13C NMR and LC-MS) and single crystal X-ray diffraction method. The compound crystallizes in the monoclinic crystal system (space group P21∖c) with unit cell dimensions a = 32.6130(12) Å, b = 7.1894(3) Å, c = 16.7673(6) Å, β = 92.539(3) °, Z = 4, and V = 3927.5(3) Å3. The asymmetric unit consists of two title molecules (A∖B) and the intramolecular hydrogen bonds of the type CH⋯O (A∖B: S(5) ring motif) are observed. The crystal structure is stabilized with CH⋯O (A∖B: C9 chains) intermolecular hydrogen bonds and short contacts of the type CH … π (A∖B). The intercontacts in the crystal packing were analyzed using Hirshfeld surfaces method using 2D finger print plots and enrichment ratio (E). The major intercontact contributing to the Hirshfeld surfaces are found to be from H⋯H, O⋯H and C⋯H (A∖B). The favourable contacts responsible for crystal packing (A∖B) are H⋯H, C⋯H, O⋯H and C⋯C confirmed with E values. In addition, the 3D-topology of the crystal packing is analyzed and visualized. The dispersion energy framework contribution is greater than the electrostatic energy frameworks.

Synthesis of silicon-containing macrocyclic compounds by using intramolecular [2+2] photocycloaddition reactions of bis-dimethylsilyl-linked styrenes and stilbenes

A method for the synthesis of silicon-containing macrocyclic compounds, using intramolecular [2 + 2] photocycloaddition reactions of bis-dimethylsilyl-linked styrene or stilbene derivatives, is described. Photoirradiation of benzene solutions of o- and m-bis(dimethylsilylmethyl)benzene derivatives, containing two styrene units, promotes efficient formation of intramolecular [2 + 2] photocycloadducts. In contrast, photoreaction of the corresponding para-substituted analog generates only dimers. Photoreactions of bis(dimethylsilylmethyl)benzene derivatives, possessing two stilbene units produce intramolecular [2 + 2] photocycloadducts along with products of cis-trans photoisomerization. The efficiencies of these intramolecular photoreactions depend on the distances between two double bonds undergoing [2 + 2] cycloaddition. Triplet-sensitized photoreactions of the stilbene derivatives lead to cis-trans isomerization exclusively. Finally, photoreactions of the stilbene derivatives in the presence of molecular oxygen produce phenanthrene derivatives as side products.

Efficient monooxygenase-catalyzed piceatannol production: Application of cyclodextrins for reducing product inhibition

Piceatannol is a rare, costly plant-based stilbene derivative and exhibits various health-enhancing properties. Recently, we demonstrated that piceatannol could be produced from resveratrol through site-selective hydroxylation using Escherichia coli cells expressing the monooxygenase HpaBC. However, piceatannol production ceased at approximately 25mM, even when sufficient levels of the substrate resveratrol remained in the reaction mixture. In this study, we found that high concentrations (>20-25mM) of piceatannol significantly inhibited the HpaBC-catalyzed reaction. Cyclodextrins (CDs) reportedly encapsulate various hydrophobic compounds. We found that the addition of β-CD or γ-CD to the reaction mixture reduced the inhibition caused by the product piceatannol. The effects of β-CD on piceatannol production were more pronounced than those of γ-CD at high concentrations of the substrate resveratrol and CDs. The production of piceatannol reached 49mM (12gL-1) in the presence of β-CD, a level twice that achieved in the absence of β-CD. The technique described here might be applicable to the bioproduction of other stilbenes and structurally related compounds.

Immobilized triazine bis[mercapto amine] complexes of Pd(0) anchored nickel ferrite as a nanocatalyst for C–C coupling reaction

Immobilized triazine bis[mercapto amine] complexes of Pd(0) (NiFe2O4@TABMA-Pd(0)) was easily synthesized and applied as highly efficient and versatile nanocatalyst for the synthesis of various trans stilbenes with high performance for the Heck coupling reaction of several types of aryl halides under thermal conditions. In short reaction time, excellent yields of trans stilbene derivatives have been achieved using NiFe2O4@TABMA-Pd(0) catalyst.

Stereocontrolled synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction

A general procedure for the stereocontrolled synthesis of (E)-stilbene derivatives by palladium-catalyzed Suzuki-Miyaura cross-coupling reaction of (E)-2-phenylethenylboronic acid pinacol ester with aryl bromides was investigated. (E)-2-Phenylethenylboronic acid pinacol ester was prepared by 9-BBN-catalyzed hydroboration of phenylacetylene with pinacolborane. This reagent undergoes facile palladium-catalyzed cross-coupling with a diverse set of aryl bromides to provide the corresponding (E)-stilbene derivatives in moderate to good yield. The use of the sterically bulky t-Bu3PHBF4 ligand was crucial to the successful coupling of electron-rich and electron-poor aryl bromides. Complete stereochemical retention of the (E)-2-phenylethenylboronic acid pinacol ester alkene geometry was observed in all of the (E)-stilbene derivatives synthesized.

Stilbenes: Chemistry and Molecular Mechanisms of Anti-obesity

Stilbenoids, a class of plant polyphenols abundant in berries, have been found to have many biological actions. Resveratrol, the most well-known of the stilbenes, is used for disease prevention, particularly for anti-obesity. Due to the low bioavailability of resveratrol, other stilbenes and their metabolites are also considered as candidates for anti-obesity. Obesity has numerous known causes, including genetics, diet, lifestyle, the endocrine system, and gut microbiota. Treating obesity can be rather problematic, with calorie intake reductions and increased physical exercise being difficult to maintain, medicines having side effects, and surgery being not suitable for all patients. Many stilbenes tested in animal studies have demonstrated beneficial effects, including reductions of lipid accumulation, regulation of glucose homeostasis, inflammation alleviation, and modulation of gut microbiota. This paper summarizes the molecular mechanisms of four major stilbenes used to treat obesity. Several pathways involved in regulation of fat metabolism affected by stilbenes, such as adipogenesis, lipogenesis, lipolysis, thermogenesis, and gut microbiota, will be introduced. In summary, stilbenes are promising for managing and treating obesity. A comparison of the physiological effects of various stilbenoids and other stilbene derivatives on obesity-associated diseases is warranted.

Palladium-Catalyzed Decarboxylative γ-Olefination of 2,5-Cyclohexadiene-1-carboxylic Acid Derivatives with Vinyl Halides.

This study explores a Pd-catalyzed decarboxylative Heck-type Csp3-Csp2 coupling reaction of 2,5-cyclohexadiene-1-carboxylic acid derivatives with vinyl halides to provide γ-olefination products. The olefinated 1,3-cyclohexadienes can be further oxidized to produce meta-alkylated stilbene derivatives. Additionally, the conjugated diene products can also undergo a Diels-Alder reaction to produce a bicyclo[2.2.2]octadiene framework.

New Prenylated Stilbenes and Antioxidant Activities of <i>Cajanus cajan</i> (L.) Millsp. (Pigeon pea)

New Prenylated stilbene derivatives, 3-hydroxy-4-prenyl-5-methoxy-stilbene acid (1) and 5,4'-dihydroxy-3-methoxy-2-prenyl-stilbene (2) had been isolated from methanol extract of Cajanus cajan (L.) Millsp. (Pigeon pea), a member of family fabaceae. The aim of this present work was to evaluate its in vitro antioxidant activity using 2,2-diphenyl-1-picryhydrazyl (DPPH) radical-scavenging. Isolation of compounds was achieved by extraction (maceration) and chromatographic technique. The structures of the compounds were determined based on UV, IR, 1H-NMR and 13C-NMR spectra and also by comparing with the previously reported data. Antioxidant activities (IC50) of 1 and 2 were 413.68 μg/mL and 271.53 μg/mL, respectively.

White Light Induced E/Z-Photoisomerization of Diphenylamine-Tethered Fluorescent Stilbene Derivatives: Synthesis, Photophysical, and Electrochemical Investigation

A facile synthesis and detailed photophysical investigation of E/Z-isomerization of fluorescent diphenylamine tethered stilbene derivatives (DPASs) under white light exposure have been carried out to understand the effect on fluorescence, electrochemical properties, and photostability under various activation/deactivation pathways. In solution state, in the dark, the E-isomer of DPASs (6a-d) exhibited high fluorescence quantum yields (Φfl ≈ 53% to 60% in DMSO). However, on white light exposure, 1H NMR and HPLC studies revealed that pure E-isomer of the DPAS 6a (∼9.5 mM) started converting into its Z-form by photoisomerization until it reaches to nearly equilibrium. At low concentrations (∼10 μM), the absorption band of the pure E-isomer in the range of 350-450 nm gradually decreased to adopt Z-conformation 6a' until a photostationary state was reached. The structure of the E-isomer 6a was unequivocally confirmed by X-ray diffraction analysis. The synthesized DPAS compounds 6a-d possessed positive solvatochromic properties, two photon absorption properties, and good thermal stability. The electrochemical investigations using DPASs showed reversible oxidation resulting in formation of a stable radical cation. Owing to useful photophysical, electrochemical and thermal properties, these DPAS derivatives are suitable for their application in biomedical imaging as well as in fabrication of electroluminescent materials.

Two-photon actuation of crosslinked liquid-crystalline polymers utilizing energy transfer system

ABSTRACTWe prepared crosslinked azotolane liquid-crystalline polymer (LCP) films doped with a stilbene derivative (two-photon chromophore) utilizing an interpenetrating polymer network (IPN) structure. The IPN films bend toward the light source upon irradiation with femtosecond laser pulses at 600 nm, which can excite the stilbene derivative by two-photon absorption. The bending speed of the IPN films increases with the square of the laser pulse intensity, which is compelling evidence for the two-photon processes.

Anti-tubercular activity of a natural stilbene and its synthetic derivatives.

Objectives: Tuberculosis (TB) and multidrug- and extensively drug-resistant TB in particular are remaining a major global health challenge and efficient new drugs against TB are needed. This study evaluated the anti-tubercular activity of a natural stilbene and its synthetic derivatives against M. tuberculosis.Methods: Isopropylstilbene and its synthetic derivatives were analyzed for their anti-tubercular activity against M. tuberculosis ATCC 27294 as well as multidrug- and extensively drug-resistant M. tuberculosis clinical isolates by using MGIT 960 instrumentation and EpiCenter software equipped with TB eXiST module. Cytotoxic effects of drug candidates were determined by a MTT dye reduction assay using A549 adenocarcinomic human alveolar basal epithelial cells.Results: Growth of M. tuberculosis ATCC 27294 was suppressed by the natural isopropylstilbene HB64 as well as synthetic derivatives DB56 and DB55 at 25 µg/ml. Growth of clinical isolates MDR and XDR M. tuberculosis was suppressed by HB64 at 100 µg/ml as well as by synthetic derivatives DB56 and DB55 at 50 µg/ml and 25 µg/ml, respectively. No anti-tubercular activity was demonstrated for synthetic derivatives DB53, EB251, and RB57 at 100 µg/ml. Toxicity in terms of IC50 values of HB64, DB55 and DB56 were 7.92 µg/ml, 12.15 µg/ml and 16.01 µg/ml, respectively.Conclusions: Synthetical derivatives of stilbene might be effective candidates as anti-tubercular drugs. However, toxicity of these substances as determined by IC50 values might limit therapeutic success in vivo. Further investigations should address lowering the toxicity for parenteral administration by remodeling stilbene derivatives.

Room temperature columnar liquid crystalline self-assembly of acidochromic, luminescent, star-shaped molecules with cyanovinylene chromophores

Effect of cyanovinylene group on the thermal and photophysical behavior of tris(N-salicylideneanilines).

Influence of charge transfer on the isomerisation of stilbene derivatives for application in cancer therapy.

The photoisomerisation of non-toxic trans-combretastatin CA4 to its cytotoxic cis isomer demonstrates the high potential of this and similar compounds for localised cancer therapy. The introduction of intramolecular charge-transfer character by altering the substituents of combretastatin systems opens up possibilities to tailor these stilbene derivatives to the special demands of anticancer drugs. In this TDDFT study we explore how absorption wavelengths for both the trans and cis isomers can be red shifted to enable deeper light penetration into tissue and how the trans → cis and cis → trans isomerisations are affected by charge transfer effects to different degrees.

Preventing Carcinogenesis with Compounds that Inhibit Cytochrome P450 1A1 and 1B1

Cytochrome P450 1A1 and 1B1 convert polycyclic aromatic hydrocarbons to carcinogenic compounds in extrahepatic tissues. In 1997, resveratrol, a naturally occurring stilbene found in grapes and red wine, was found to inhibit the growth of tumors and that one potential mechanism was by inhibiting cytochrome P450 1A1 and 1B1. This prompted further research on various stilbene derivatives as chemopreventive agents. It has recently been discovered that aryl morpholino triazenes represent a new class of cytochrome P450 1A1 and 1B1 inhibitors opening up the field to explore another type of potential chemopreventive agent.

Computational simulations determining disulfonic stilbene derivative bioavailability within human serum albumin.

Disulfonic stilbene (DS) derivatives are a member of the large family of compounds widely employed in medicine and biology as modulators for membrane transporters or inhibitors of a protein involved in DNA repair. They constitute interesting compounds that have not yet been investigated within the bioavailability framework. No crystallographic structures exist involving such compounds embedded in the most common drug carrier, human serum albumin (HSA). The present work studies, for the first time, the physico-chemical features driving the inclusion of three DS derivatives (amino, nitro and acetamido, named DADS, DNDS and DATDS, respectively) within the four common HSA binding sites using combined molecular docking and molecular dynamics simulations. A careful analysis of each ligand within each of the studied binding sites is carried out, highlighting specific interactions and key residues playing a role in stabilizing the ligand within each pocket. The comparison between DADS, DNDS and DATDS reveals that depending on the binding site, the conclusions are rather different. For instance, the IB binding site shows a specificity to DADS compounds while IIIA is the most favorable site for DNDS and DATDS.

Synthesis and biological evaluation of stilbene derivatives coupled to NO donors as potential antidiabetic agents

The work is focused on the design of drugs that prevent and treat diabetes and its complications. A novel class of stilbene derivatives were prepared by coupling NO donors of alkyl nitrate and were fully characterised by NMR and other techniques. These compounds were tested in vitro activity, including α-glucosidase inhibitory activity, aldose reductase (AR) inhibitory activity and advanced glycation end products (AGEs) formation inhibitory activity. A class of modified compounds could play a significant effect for treatment of diabetic complications. Target compounds 3e and 7c offered a potential drug design concept for the development of therapeutic or preventive agents for diabetes and its complications.

LC-MS/MS Tandem Mass Spectrometry for Analysis of Phenolic Compounds and Pentacyclic Triterpenes in Antifungal Extracts of Terminalia brownii (Fresen).

Decoctions and macerations of the stem bark and wood of Terminalia brownii Fresen. are used in traditional medicine for fungal infections and as fungicides on field crops and in traditional granaries in Sudan. In addition, T. brownii water extracts are commonly used as sprays for protecting wooden houses and furniture. Therefore, using agar disc diffusion and macrodilution methods, eight extracts of various polarities from the stem wood and bark were screened for their growth-inhibitory effects against filamentous fungi commonly causing fruit, vegetable, grain and wood decay, as well as infections in the immunocompromised host. Ethyl acetate extracts of the stem wood and bark gave the best antifungal activities, with MIC values of 250 µg/mL against Nattrassia mangiferae and Fusarium verticillioides, and 500 µg/mL against Aspergillus niger and Aspergillus flavus. Aqueous extracts gave almost as potent effects as the ethyl acetate extracts against the Aspergillus and Fusarium strains, and were slightly more active than the ethyl acetate extracts against Nattrassia mangiferae. Thin layer chromatography, RP-HPLC-DAD and tandem mass spectrometry (LC-MS/MS), were employed to identify the chemical constituents in the ethyl acetate fractions of the stem bark and wood. The stem bark and wood were found to have a similar qualitative composition of polyphenols and triterpenoids, but differed quantitatively from each other. The stilbene derivatives, cis- (3) and trans- resveratrol-3-O-β-galloylglucoside (4), were identified for the first time in T. brownii. Moreover, methyl-(S)-flavogallonate (5), quercetin-7-β-O-di-glucoside (8), quercetin-7-O-galloyl-glucoside (10), naringenin-4′-methoxy-7-pyranoside (7), 5,6-dihydroxy-3′,4′,7-tri-methoxy flavone (12), gallagic acid dilactone (terminalin) (6), a corilagin derivative (9) and two oleanane type triterpenoids (1) and (2) were characterized. The flavonoids, a corilagin derivative and terminalin, have not been identified before in T. brownii. We reported earlier on the occurrence of methyl-S-flavogallonate and its isomer in the roots of T. brownii, but this is the first report on their occurrence in the stem wood as well. Our results justify the traditional uses of macerations and decoctions of T. brownii stem wood and bark for crop and wood protection and demonstrate that standardized extracts could have uses for the eco-friendly control of plant pathogenic fungi in African agroforestry systems. Likewise, our results justify the traditional uses of these preparations for the treatment of skin infections caused by filamentous fungi.

Estrogenic Active Stilbene Derivatives as Anti-Cancer Agents: A DFT and QSAR Study.

Exploring different quantum chemical quantities for lead compounds is an ongoing approach in identifying crucial structural activity related features that are contributing into their biological activities. Herein, activity-related quantum chemical calculations were performed for the selected estrogenic stilbene derivatives using density functional theory (DFT) with B3LYP functional and 6-311++G** basis set. In addition, specific activity-related geometry-independent drug-like properties are discussed for these derivatives. To obtain the mathematical model that correlates the chemical descriptors with their measured estrogenic activities, the quantitative structure activity relationship (QSAR) is established using multiple linear regression (MLR) and support vector regression (SVR) methods. Satisfactory fit with a reasonable regression correlation coefficient (${\rm{R}}^{2}= 0.78$R2=0.78) between predicted and experimental $pEC_{50}$pEC50 values is observed using MLR method. The present study identifies the essential physicochemical descriptors that effectively contribute in the estrogenic activity. The applied approach provides helpful insight into the designing novel estrogenic agents with improved anticancer activities.