Stilbene Derivatives Research Articles

The Aryl Hydrocarbon Receptor and Its Crosstalk: A Chemopreventive Target of Naturally Occurring and Modified Phytochemicals.

The aryl hydrocarbon receptor (AhR) is an environmentally sensitive transcription factor (TF) historically associated with carcinogenesis initiation via the activation of numerous carcinogens. Nowadays, the AhR has been attributed to multiple endogenous functions to maintain cellular homeostasis. Moreover, crosstalk, often reciprocal, has been found between the AhR and several other TFs, particularly estrogen receptors (ERs) and nuclear factor erythroid 2-related factor-2 (Nrf2). Adequate modulation of these signaling pathways seems to be an attractive strategy for cancer chemoprevention. Several naturally occurring and synthetically modified AhR or ER ligands and Nrf2 modulators have been described. Sulfur-containing derivatives of glucosinolates, such as indole-3-carbinol (I3C), and stilbene derivatives are particularly interesting in this context. I3C and its condensation product, 3,3'-diindolylmethane (DIM), are classic examples of blocking agents that increase drug-metabolizing enzyme activity through activation of the AhR. Still, they also affect multiple essential signaling pathways in preventing hormone-dependent cancer. Resveratrol is a competitive antagonist of several classic AhR ligands. Its analogs, with ortho-methoxy substituents, exert stronger antiproliferative and proapoptotic activity. In addition, they modulate AhR activity and estrogen metabolism. Their activity seems related to a number of methoxy groups introduced into the stilbene structure. This review summarizes the data on the chemopreventive potential of these classes of phytochemicals, in the context of AhR and its crosstalk modulation.

Efficacy of Stilbene Derivatives in Sensitizing Breast Cancer Cells to Ionizing Radiation.

One of the treatments for breast cancer is surgical resection of the tumour and prevention of recurrence with postoperative radiotherapy. Unfortunately, radiotherapy is not always effective enough due to the low sensitivity of cancer cells to ionising radiation. This study aimed to evaluate the radiosensitising properties of resveratrol, piceatannol and polydatin on breast cancer cells, which differ in the presence of hormonal receptors on their surface. The experimental part was carried out on triple-negative breast cancer cells (HCC38) and hormone-dependent cells (MCF7). The study assessed the level of cell death, changes in the expression of genes (BAX, BCL-2) and proteins related to the apoptosis process (CASPASE 3, 8 and P53), changes in the expression of antioxidant enzymes (CATALASE, SOD, GPx1/2) and NRF-2. Additionally, the expression level of RAD51 protein and histone H2AX, which are involved in DNA repair processes, was assessed. Statistical significance was evaluated by a two-way analysis of variance (ANOVA) followed by Tukey's post hoc test (p < 0.05). Ionising radiation in combination with resveratrol or piceatannol activates the apoptosis process by internal and external pathways. Greater sensitivity of MCF7 cells compared to HCC38 cells to ionising radiation in combination with resveratrol is associated with a weaker antioxidant response of cells and reduced intensity of DNA damage repair. DNA repair induced by ionising radiation occurs more effectively in HCC38 cells than in MCF7 cells. Resveratrol has the highest radiosensitising potential among the tested stilbene for cells of both lines. The effectiveness of ionizing radiation in combination with resveratrol (to a lesser extent with piceatannol) is more significant in MCF7 than in HCC38 cells.

Hydrogen bonding to the electron accepting group controls the absorption spectrum of a push–pull stilbene adsorbed on amorphous silica

The photophysical and photochemical properties of push–pull photoswitches, such as stilbene derivatives, are very sensitive to their surroundings, allowing, e.g., for the control of the spectral properties or alternatively for probing the molecular environment. Here, we investigate how various adsorption motifs of 4-(N, N-Dimethylamino)-4’-nitrostilbene (DANS) on an amorphous glass surface influence its absorption spectra. Particular attention is given to the prominent first bright charge transfer state and the factors governing these modifications. The absorption spectra is simulated using time-dependent density functional theory on a large set of adsorption geometries that exhibit different kinds of molecule–surface interactions. We find that C–H⋯O interactions of the methyl or phenyl moieties with the glass affect the spectrum only marginally, whereas the dispersion interaction of the π system with the surface tends to diminish the intensity of the first absorption band. Moreover, an enhancement of the push–pull properties of DANS and a significant redshift occur whenever O–H⋯O hydrogen bonds with the NO2 group are present, whereas a hydrogen bond O–H⋯N to the NMe2 group results in a blueshift.

Synthesis, In silico Study and Cytotoxicity Evaluation of Some Newly Synthesized Stilbene Derivatives

Synthesis, In silico Study and Cytotoxicity Evaluation of Some Newly Synthesized Stilbene Derivatives

Chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling enabled by palladium catalysis: Reaction development and mechanism studies

Transition metal-catalyzed cross-electrophile coupling of two electrophiles has proved to be a powerful and step-economic strategy for the construction of C–C bonds in organic synthesis. Despite the considerable advances, cross-electrophile coupling of sp2-hybridized carboxylic acid derivatives via a decarbonylative fashion remains a formidable challenge. Herein, we disclose a chemoselective C(sp2)–C(sp2) doubly decarbonylative cross-electrophile coupling of aroyl fluorides with a wide range of aryl and alkenyl thioesters by palladium catalysis. The catalytic protocol provides an alternative route for the efficient synthesis of biaryls and stilbene derivatives owing to wide accessibility, natural abundance and stability of carboxylic acid and relevant derivatives. The combination of a series of experiments and theoretical calculations reveals that conversion of aroyl fluorides into the corresponding thioesters, chloride anion in catalyst PdCl2 and in situ generated Zn(II) reagents play the crucial roles in the current cross-coupling reactions.

Chemical Composition, Antioxidant, and Cytotoxic Effects of Senna rugosa Leaf and Root Extracts on Human Leukemia Cell Lines.

Senna rugosa is a species found in the Cerrado and used in folk medicine as a vermifuge and in the treatment of poisonous snakebites accidents. In this work, we identified the main secondary metabolites present in ethanolic extracts of the leaves (ELSR) and roots (ERSR) of S. rugosa and evaluated the potential cytoprotective effect against cellular macromolecular damage, as well as the cytotoxic properties of the extracts on the K562 and Jurkat leukemic cell lines. The identification of metabolites was carried out by liquid chromatography coupled with mass spectrometry. The antioxidant activities were investigated by direct ABTS•+ and DPPH• radical scavenging methods, protection against oxidative damage in proteins, and DNA. Cytotoxic properties were investigated against healthy cells, isolated from human peripheral blood (PBMC) and leukemic cell lines. The leaf extracts contained catechin, rutin, epigallocatechin derivatives, kaempferol glycosides, luteolin, and dimeric and trimeric procyanidins, while the root extract profile showed obtusichromoneside derivatives, 2-methoxystypandrone, stilbene derivatives, naphthopyranones, and flavanone derivatives. The extracts showed antioxidant activity, with an IC50 of 4.86 ± 0.51 μg/mL and 8.33 ± 0.90 μg/mL in the ABTS assay for ELSR and ERSR, respectively. Furthermore, in the DPPH• assay, the IC50 was 19.98 ± 1.96 μg/mL for ELSR and 13.37 ± 1.05 μg/mL for ERSR. The extracts protected macromolecules against oxidative damage at concentrations of 5 μg/mL. The cytotoxicity test against leukemic strains was observed after 24 and 48 h of treatment. After 48 h, results against the K562 cell line demonstrate an IC50 of 242.54 ± 2.38 μg/mL and 223.00 ± 2.34 μg/mL for ELSR and ERSR, respectively. While against the Jurkat cell line, these extracts showed an IC50 of 171.45 ± 2.25 μg/mL and 189.30 ± 2.27 μg/mL, respectively. The results pertaining to PBMC viability demonstrated that the extracts showed selectivity for the leukemic cell lines. Together, our results reveal that the leaves and roots of S. rugosa have completely distinct and complex chemical compositions and expand their significant pharmacological potential in oxidative stress and leukemia conditions.

Characterization and Application of Cyrene as a Biomass-Based Solvent for Homogeneous Heck-Coupling Reaction.

Cyrene, a renewable, non-toxic substance having negligible vapor pressure, even at high temperatures, was proposed as a reaction medium for homogeneous Pd-catalyzed Heck-coupling reactions. It was first characterized by its temperature-dependent physicochemical properties, i.e., vapor pressure, density, surface tension, heat capacity, and viscosity, the key parameters of its reaction and process chemistry. Its refractive indices in the function of temperature were also determined. Hereafter, the effect of reaction parameters (Pd source, nature of the base, the water content of the reaction mixture, leaving group (-I, -Br, -Cl, and -OTf of aromatic substrates) on Pd-catalyzed Heck-coupling reaction was investigated using iodobenzene and styrene as model substrates. Subsequently, 4-substituted iodobenzene and styrene derivatives were applied to investigate the effect of electronic parameters on the reaction efficiency and functional group tolerance. To demonstrate the applicability of the system, thirteen stilbene derivatives were isolated with good to high yields and purity (> 95%) using 0.2 mol% of Pd, 1.5 eq. of Et3N as a base, in 1 mL of Cyrene for 2 h at 100 °C.

A Comprehensive Review on History, Sources, Biosynthesis, Chemical Synthesis and Applications of Stilbenes

Abstract: This review is about a class of plant polyphenols known as Stilbenes. Resveratrol – the first stilbene was extracted from White Hellebore in 1940, since then 400 plus stilbene derivatives have been discovered. The core purpose of this paper is to summarize the history, extraction sources, biosynthesis and chemical synthesis and applications of stilbenes. Apart from biosynthesis, its novel derivatives are being synthesized in laboratories. This class of compounds has extensive clinical (including antioxidant, anticancer, anti-inflammatory activities etc.) and industrial applications such as optical dyes, laser dyes, scintillators, etc.

Medicinal chemistry perspective on the structure-activity relationship of stilbene derivatives.

Stilbenes are a small family of polyphenolic secondary metabolites produced in a variety of closely related plant species. These compounds function as phytoalexins, aiding plant defense against phytopathogens and plants' adaptation to abiotic environmental factors. Structurally, some important phenolic compounds have a 14-carbon skeleton and usually have two isomeric forms, Z and E. Stilbenes contain two benzene rings linked by a molecule of ethanol or ethylene. Some derivatives of natural (poly)phenolic stilbenes such as resveratrol, pterostilbene, and combretastatin A-4 have shown various biological activities, such as anti-microbial, anti-cancer, and anti-inflammatory properties as well as protection against heart disease, Alzheimer's disease, and diabetes. Among stilbenes, resveratrol is certainly the most popular and extensively studied for its health properties. In recent years, an increasing number of stilbene compounds have been investigated for their bioactivity. This review focuses on the assessment of synthetic stilbene derivatives in terms of their biological activities and structure-activity relationship. The goal of this study is to consider the structural changes and different substitutions on phenyl rings that can improve the desired medicinal effects of stilbene-based compounds beyond the usual standards and subsequently discover biological activities by identifying effective alternatives of the evaluated compounds.

Study of phenoxy radical couplings using the enzymatic secretome of Botrytis cinerea.

Phenoxy radical coupling reactions are widely used in nature for the synthesis of complex molecules such as lignin. Their use in the laboratory has great potential for the production of high value compounds from the polyphenol family. While the enzymes responsible for the generation of the radicals are well known, the behavior of the latter is still enigmatic and difficult to control in a reaction flask. Previous work in our laboratory using the enzymatic secretome of B. cinerea containing laccases has shown that incubation of stilbenes leads to dimers, while incubation of phenylpropanoids leads to dimers as well as larger coupling products. Building on these previous studies, this paper investigates the role of different structural features in phenoxy radical couplings. We first demonstrate that the presence of an exocyclic conjugated double bond plays a role in the generation of efficient reactions. In addition, we show that the formation of phenylpropanoid trimers and tetramers can proceed via a decarboxylation reaction that regenerates this reactive moiety. Lastly, this study investigates the reactivity of other phenolic compounds: stilbene dimers, a dihydro-stilbene, a 4-O-methyl-stilbene and a simple phenol with the enzymatic secretome of B. cinerea. The observed efficient dimerization reactions consistently correlate with the presence of a para-phenol conjugated to an exocyclic double bond. The absence of this structural feature leads to variable results, with some compounds showing low conversion or no reaction at all. This research has allowed the development of a controlled method for the synthesis of specific dimers and tetramers of phenylpropanoid derivatives and novel stilbene derivatives, as well as an understanding of features that can promote efficient radical coupling reactions.

A Single Terminal [NiII-OH] Catalyst for Direct Julia-Type Olefination and α-Alkylation Involving Sulfones and Alcohols.

A terminal [NiII-OH] complex 1, supported by triflamide-functionalized NHC ligands, showed divergent reactivity for the reaction of sulfone with alcohol, contingent on base concentration, temperature, and time. Julia-type olefination of alcohols with sulfones was achieved using one equiv. of base, whereas lowering base loading to 0.5 equiv. afforded α-alkylated sulfones. Besides excellent substrate scope and selectivity, biologically active stilbene derivatives DMU-212, pinosylvin, resveratrol, and piceatannol were synthesized in high yield under Julia-type olefination conditions. An extensive array of controlled experiments and DFT calculations provide valuable insight on the reaction pathway.

Stilbene derivatives from Gnetum montanum Markgr. with their xanthine oxidase inhibition activity

AbstractPhytochemical study on the methanol extract of the trunks of Gnetum montanum Markgr. led to the isolation of one new stilbene derivative, (E)‐2′‐methoxy‐3,5,5′‐trihydroxystilbene (1) and six known compounds, lehmbachol (2), gnetulin (3), trans‐shegansu B (4), cis‐shegansu B (5), (+)‐hannokinol (6), and gnetol (7). Their chemical structures were determined by spectroscopic analyses including HR‐ESI‐MS, 1D and 2D NMR, and circular dichroism methods in comparison with the reported data. In addition, compounds 1–5 showed xanthine oxidase inhibitory activity with IC50 values of 13.6, 35.2, 38.7, 43.4, and 47.7 µm, respectively, compared to the positive control, allopurinol, which showed IC50 value of 2.9 µm.

A new flavonostilbene glycoside and four new stilbene derivatives from the roots of Polygonum multiflorum

One new flavonostilbene glycoside, polygonflavanol C (1), two new dimeric stilbene glycosides, multiflorumiside M and multiflorumiside N (2−3), one new diphenyl ethanol glycoside, (R)-2,3,5,4′-tetrahydroxy-diphenylethanol 2-O-β-D-glucopyranoside (4), and one new deoxybenzoin glycoside, 2,4,3′,5′-tetrahydroxy-6-methyl-deoxybenzoin 2-O-β-D-glucopyranoside (5), together with six known ones (6−11), were isolated from the roots of Polygonum multiflorum. Their structures were elucidated by the comprehensive spectroscopic analyses. In addition, compounds 1 and 7 showed significantly in vitro anti-inflammatory activity.

Cytotoxic prenylated phenols of false indigo-bush (Amorpha fruticosa L.)

This study employed the MTT assay to assess the cytotoxicity of one flavan and two stilbene derivatives isolated from the false indigo-bush (Amorpha fruticosa L.) fruits: 5,7-dihydroxy-8-geranylflavanone (1), 2-carboxy-3,5-dihydroxy-4-geranylbibenzyl (2), and 2-carboxy-3-hydroxy-4-prenyl-5-methoxybibenzyl (3). The examined compounds reduced the survival of human cervical and colon tumour cells (HeLa, HT-29, HCT-116, and LS174) with IC50 values ranging from 10.55 to 147.09 μg/mL, except for 1, which did not affect LS174 cells within the tested concentrations. The highest activity was observed for 1 against HeLa cells, and 1 also exhibited the weakest effect against normal foetal lung fibroblasts (IC50 = 166.11 μg/mL), demonstrating good potency and selectivity. Stilbenes 2 and 3 proved efficacious, but lacked selectivity compared to 1. Our findings revealed the cytotoxicity of false indigo-bush constituents, justifying further mechanistic and in vivo investigations, particularly on 5,7-dihydroxy-8-geranylflavanone, which displayed considerable in vitro anticancer capacity and a potentially favourable safety profile.

Elucidation of Stilbene-Derivatives as Potential Inhibitors of SARS-CoV-2 Mpro Binding Pocket: A Molecular Docking, and ADMET Prediction Studies

Berries are well-known not only for their flavour and nutritional content but also for the potential health effects of their bioactive components. Stilbenes, a class of phenolic compounds found in berries, have essential pharmacological activities in many biological pathways. The COVID-19 pandemic had put many countries in the world in a state of chaos. Although the prevalence of COVID-19 seems to have subsided, the search for the remedy to overcome this pathogen is still ongoing. Plant-derived substances have well been recorded to display potent effects including antiviral activity. Hence, the aim of this study is to determine the potential of stilbene derivatives to act as antiviral agents against COVID-19. In silico molecular docking method was employed to elucidate the structural interaction of eleven stilbene derivatives to SARS-CoV-2 Mpro binding pocket using CB-Dock2 server, followed by drug-likeness and ADMET prediction analysis. Based on the docking score and ligand-receptor interactions, rhaponticin and polydatin had the best vina docking scores for the SARS-CoV-2 Mpro pocket with -8.1 kcal/mol and -8.0 kcal/mol respectively. These scores were found to be lower than controls, remdesivir (-7.8 kcal/mol) and inhibitor N3 (-7.9 kcal/mol), indicating its high affinity towards the binding target. In conclusion, the study identified that rhaponticin and polydatin might serve as potential lead compounds for developing new SARS-CoV-2 drugs. However, these results need to be validated by in vitro and in vivo experimental studies before these compounds can be considered for further development as antiviral agents.

Photoinduced [2+2] and [4+4] Cycloaddition and Cycloreversion Reactions for the Development of Photocontrollable DNA Binders

AbstractIn the current field of photopharmacology, molecular photoswitches are applied whose interactions with DNA can be triggered or controlled by light. And although several photochromic reactions have been shown to serve this purpose well, the reversible photocycloaddition and photocycloreversion reactions have been largely neglected. This absence of research is surprising because especially the photodimerization of a DNA ligand leads to products with significant change of the size and shape which, in turn, leads to strongly diminished or even suppressed DNA association. Therefore, photocycloaddition–cycloreversion sequences have a huge potential for the photoinduced, reversible deactivation and activation of ligand–DNA interactions, as will be shown with selected examples in this Concept Article. Specifically, heterostyryl and ‐stilbene derivatives are presented whose DNA–binding properties are efficiently switched in reversible [2+2] photocycloaddition reactions. In addition, the photocontrolled DNA–binding of anthracene derivatives and their heterocyclic benzo[b]quinolizinium analogues in a [4+4] photocycloaddition, as well as the use of this reaction as part of dual–mode switches in combination with redox‐active functionalities, are highlighted. Furthermore, examples of conjugates are provided, in which the photochromic unit is bound covalently to nucleic acids or proteins, such that the photocycloaddition reaction can be used for reversible photoinduced crosslinking, ligation, or inhibition of gene expression.

Identification and nitric oxide production inhibitory activity of phenolic derivatives from the trunks of Gnetum latifolium

Phytochemical investigation of the trunks from Gnetum latifolium led to the isolation of a novel phenolic glucoside, 2E-2,4-di-(3,4-dihydroxyphenyl)but-2-en-1-yl-O-β-D-glucopyranoside (1), along with five known stilbene derivatives (2–6). Their structures were determined mainly using high-resolution electrospray ionisation mass spectrometry and nuclear magnetic resonance spectroscopic analyses, followed by comparisons of observed spectral data with reported values. The novel compound 1 in G. latifolium was found to be useful as a chemotaxonomic marker. Biological evaluation revealed that compound 6 had remarkable inhibitory effects on nitric oxide production, with a half-maximal inhibitory concentration (IC50) value of 4.85 ± 0.20 µM, which was much higher than that of the positive control dexamethasone (IC50 = 14.20 ± 0.54 µM).

Mechanistic insights into inhibition of CCL2-guided leukocyte recruitment by oxyresveratrol and its derivatives

Inflammatory responses are the outcomes of coordinated interactions amongst chemokines and their exclusive non-negotiable counterparts such as glycosaminoglycans and GPCRs. CCL2 in conjunction with other immune molecules positively regulates the migration, infiltration, and recruitment of macrophages to the site of inflammation, hence is a promising target from pharmaceutical perspective. Stilbenes such as resveratrol and its derivatives are well documented for their anti-inflammatory responses. The current study presents a structure-based screening and unravels the molecular recognition patterns of stilbene derivatives against CCL2 chemokine to identify their potential to interact and inhibit the proinflammatory activity of CCL2. Structure based in silico screening of aglycosidic stilbenes followed by fluorescence, NMR and in vitro chemotaxis experiments established that oxyresveratrol (ORS), a symmetrical hydroxylated stilbene, prominently binds CCL2 and inhibits macrophage migration. Further, extensive computational analysis reveals the atom level details of molecular recognition events on ORS and its two derivatives ORS10/ORS16, whereby ORS16 demonstrated as a superior CCL2 binding counterpart. Indeed, NMR and computational analysis suggested that ORS interacts through the receptor binding site of CCL2 to attenuate the leukocyte migration. In brief, the current study provides a basis for designing potential inhibitors opting ORS, and more precisely ORS16 as a primary architecture for targeting CCL2-mediated inflammatory proceedings.

Transcriptome Analysis Reveals Anti-Cancer Effects of Isorhapontigenin (ISO) on Highly Invasive Human T24 Bladder Cancer Cells.

Bladder cancer, the most common malignancy of the urinary tract, has a poor overall survival rate when the tumor becomes muscle invasive. The discovery and evaluation of new alternative medications targeting high-grade muscle invasive bladder cancer (MIBC) are of tremendous importance in reducing bladder cancer mortality. Isorhapontigenin (ISO), a stilbene derivative from the Chinese herb Gnetum cleistostachyum, exhibits a strong anti-cancer effect on MIBCs. Here, we report the whole transcriptome profiling of ISO-treated human bladder cancer T24 cells. A total of 1047 differentially expressed genes (DEGs) were identified, including 596 downregulated and 451 upregulated genes. Functional annotation and pathway analysis revealed that ISO treatment induced massive changes in gene expression associated with cell movement, migration, invasion, metabolism, proliferation, and angiogenesis. Additionally, ISO treatment-activated genes involved in the inflammatory response but repressed genes involved in hypoxia signaling, glycolysis, the actin cytoskeleton, and the tumor microenvironment. In summary, our whole transcriptome analysis demonstrated a shift in metabolism and altered actin cytoskeleton in ISO-treated T24 cells, which subsequently contribute to tumor microenvironment remodeling that suppresses tumor growth and progression.

Functionalized cyanostilbene-based nano-AIEgens: multipoint binding interactions for improved sensing of gallic acid in real-life food samples.

Cyano-substituted stilbene (CSS) derivatives have been synthesized that can form luminescent nanoscopic assemblies in an aqueous medium. The optical properties of such materials, as governed by the relative ratios of their monomer and aggregated forms, are found to be susceptible to pH and temperature of the medium. The compound with boronic acid attached at the terminal positions shows a turn-on fluorescence response (LOD: 15.4 ppb) with gallic acid (GA). The mechanistic studies indicate that the 1,2-diol unit of GA is involved in ester formation with the boronic acid residue, while the carboxylic end engages in hydrogen bonding interaction with the nitrile unit. Such multi-point binding interaction provides better selectivity over other structurally similar analytes. Moreover, the distinct aggregation properties of such boronate ester derivatives are responsible for the GA-specific optical response. The sensory system has been utilized for the determination of the levels of GA derivatives in tea (green tea and black tea) and various fruit (mango, orange, guava, pomegranate) extracts. In all cases, the estimated values of GAE were found to be in the same range reported by others. Finally, low-cost, chemically-modified paper strips have been designed for rapid, on-location detection of GA.