Stilbene Derivatives Research Articles

Reactivity and Mechanistic Issues in the Photocyclization of Dihalostyryl‐Naphthalenes towards Halo‐[4]helicenes: A Transposition on a Mallory Theme

AbstractOne of the most straightforward strategies nowadays for the synthesis of carbo‐ and hetero‐helicenes is the oxidative photocyclization of stilbene derivatives under Mallory conditions. In this study, the reactivity of a series of 3,4‐dihalostyryl‐naphthalenes (Hal=Br, F and Cl) has been investigated using Mallory conditions towards the corresponding halogenated [4]helicene compounds. The difluoro precursor afforded the two isomeric 2,3‐ and 1,2‐difluoro‐[4]helicenes, resulting from the ring closure on the two possible positions of the substituted benzene ring, the dichloro compound led to the formation of a mixture of the two isomeric 2,3 and 1,2‐dichloro‐[4]helicenes together with the 2‐mono‐chloro derivative, while the dibromo precursor provided, unexpectedly, only 2,3‐dibromo‐[4]helicene and the 2‐mono‐bromo derivative. DFT calculations performed on the entire series of precursors, final helicenes and intermediate dihydrohelicenes, including the non‐halogenated congeners, reveal the highly energetically favorable formation of a second dihydrohelicene intermediate following a [1,9]‐hydrogen sigmatropic transposition. Whereas the existence of this transposed dihydrohelicene intermediate, more stable than the initially formed dihydrohelicene by 15–30 kcal/mol, was until now “hidden” in the non‐substituted series, it allows herein to explain its re‐aromatization through formal elimination of HX in order to provide the 2‐mono‐halogenated‐[4]helicene derivatives.

A novel stilbene derivative (GMQ3) suppressed proliferation and induced apoptosis in lung cancer via the p38-MAPK/SIRT1 pathway

BackgroundLung cancer is the primary cause of cancer-related mortality worldwide. The anticancer effect of stilbene has been noted in various tumor types. GMQ3, which has a stilbene-mimicking skeleton, is a novel small-molecule compound with promising antitumor activity. Our results revealed that GMQ3 not only suppressed cell proliferation and cell migration of lung cancer cells but also led to G1 phase cell cycle arrest and triggered caspase-dependent apoptosis. Furthermore, investigation of the molecular mechanism showed that GMQ3 could inhibited proliferation and induced apoptosis via the p38-MAPK/SIRT1 pathway both in vitro and in vivo. Xenograft tumor mouse models showed that GMQ3 significantly inhibited tumor growth in vivo without affecting body weight. Our findings indicated that GMQ3 exerts a strong anticancer action by suppressing cell proliferation, inhibiting cell migration and inducing cell apoptosis. Moreover, the efficacy of GMQ3 was enhanced in the presence of CDK4/6 inhibitor Abemaciclib. We conclude that GMQ3 is a promising agent with potential for lung cancer.

The Bark of Picea abies L., a Waste from Sawmill, as a Source of Valuable Compounds: Phytochemical Investigations and Isolation of a Novel Pimarane and a Stilbene Derivative.

In this work, the sawmill waste from Picea abies debarking was considered as source of valuable phytoconstituents. The extraction was performed using different ethanol/water mixtures, and characterization was obtained by LC-MSn. This latter revealed flavonoid glycosides, lignans, and procyanidins. Extraction with organic solvents (dichloromethane and methanol) and chromatographic separations of the obtained extracts by silica column followed by semi-preparative HPLC led to the isolation of polyphenols and terpenoids such as 21α-metoxy-serrat-14-en-3-one, 21α-hydroxy-serrat-14-en-3-one, pinoresinol, dehydroabietic acid, 15-hydroxy-dehydroabietic acid, 7-oxo-dehydroabietic acid, pimaric acid, 9β-pimara-7,15-dien-19-ol, 13-epi-manoyl oxide, taxifolin-3′-O-glucopyranoside, trans-astringin, and piceasides. Piceaside V and 9β-pimara-7-keto-19β-olide, two novel compounds identified for the first time in P. abies bark, were isolated, and their structures were elucidated using 1D and 2D NMR and MS techniques. The polyphenolic composition of the methanolic portion was also investigated using LC-MSn, and the piceaside content was estimated. To assess the antioxidant activity of main constituents, semi-preparative HPLC was performed on the methanolic extract, and the obtained fractions were assayed by using the DPPH test. Overall, this work shows the potential usefulness of P. abies bark as a source of valuable phytochemicals.

Review on target domains and natural compound-based inhibitors of fatty acid synthase for anticancer drug discovery.

Cancer cells require a higher amount of energy in the form of fatty acids for their uncontrolled proliferation and growth. Fatty acid synthase (FASN) plays a crucial role in the synthesis of palmitate, which is involved in most of the critical malignant pathways. Hence, by targeting FASN, tumour growth can be controlled. By designing and developing FASN inhibitors with catalytic domain specificity, safe and potential anticancer drugs can be achieved. The article draws light towards the catalytic domains of FASN, their active site residues and interaction of some of the reported natural FASN inhibitors (resveratrol, lavandulyl flavonoids, catechins, stilbene derivatives, etc). The rationality (structure-activity relationship) behind the variation in the activity of the reported natural FASN inhibitors (butyrolactones, polyphenolics, galloyl esters and thiolactomycins) has also been covered. Selective, safe and potentially active FASN inhibitors could be developed by: (i) having proper understanding of the function of all catalytic domains of FASN (ii) studying the upstream and downstream FASN regulators (iii) identifying cancer-specific FASN biomarkers (that are non-essential/absent in the normal healthy cells) (iv) exploring the complete protein structure of FASN, e-screening of the compounds prior to synthesis and study their ADME properties (v) predicting the selectivity based on their strong affinity at the catalytic site of FASN.

Resveratrol and related stilbene derivatives induce stress granules with distinct clearance kinetics.

Stress granules (SGs) are ribonucleoprotein functional condensates that form under stress conditions in all eukaryotic cells. Although their stress-survival function is far from clear, SGs have been implicated in the regulation of many vital cellular pathways. Consequently, SG dysfunction is thought to be a mechanistic point of origin for many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Additionally, SGs are thought to play a role in pathogenic pathways as diverse as viral infection and chemotherapy resistance. There is a growing consensus on the hypothesis that understanding the mechanistic regulation of SG physical properties is essential to understanding their function. Although the internal dynamics and condensation mechanisms of SGs have been broadly investigated, there have been fewer investigations into the timing of SG formation and clearance in live cells. Because the lifetime of SG persistence can be a key factor in their function and tendency toward pathological dysregulation, SG clearance mechanisms deserve particular attention. Here we show that resveratrol and its analogues piceatannol, pterostilbene, and 3,4,5,4′-tetramethoxystilbene induce G3BP-dependent SG formation with atypically rapid clearance kinetics. Resveratrol binds to G3BP, thereby reducing its protein–protein association valency. We suggest that altering G3BP valency is a pathway for the formation of uniquely transient SGs.

Heteroaryl-Ethylenes as New Lead Compounds in the Fight against High Priority Bacterial Strains.

The widespread use of antibiotics has led to a gradual increase in drug-resistant bacterial infections, which severely weakens the clinical efficacy of antibacterial therapies. In recent decades, stilbenes aroused great interest because of their high bioavailability, as well as their manifold biological activity. Our research efforts are focused on synthetic heteroaromatic stilbene derivatives as they represent a potentially new type of antibiotic with a wide antibacterial spectrum. Herein, a preliminary molecular modeling study and a versatile synthetic scheme allowed us to define eight heteroaromatic stilbene derivatives with potential antimicrobial activity. In order to evaluate our compound’s activity spectrum and antibacterial ability, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) tests have been performed on Gram-positive and Gram-negative ATCC strains. Compounds PB4, PB5, PB7, and PB8 showed the best values in terms of MIC and were also evaluated for MBC, which was found to be greater than MIC, confirming a bacteriostatic activity. For all compounds, we evaluated toxicity on colon-rectal adenocarcinoma cells tumor cells (CaCo2), once it was established that the whole selected set was more active than 5-Fluorouracil in reducing CaCo-2 cells viability. To the best of our knowledge, the biological assays have shown for these derivatives an excellent bacteriostatic activity, compared to similar molecular structures previously reported, thus paving the way for a new class of antibiotic compounds.

Synthesis, Bioactivity, and QSAR Study of 3,4-Dichlorophenyl Isoxazole-Substituted Stilbene Derivatives against the Phytopathogenic Fungus Botrytis cinerea.

Gray mold, caused by Botrytis cinerea, is one of the most destructive fungal diseases in crops, responsible for significant economic losses. In search of natural product-based fungicides, we designed and synthesized a series of novel 3,4-dichlorophenyl isoxazole-substituted stilbene derivatives, and their in vivo antifungal activities against B. cinerea were evaluated. The results indicated that some of the target molecules demonstrated remarkable efficiency for the control of tomato gray mold. In particular, compound 5r displayed the highest fungicidal potency with an inhibition rate of 56.11% comparable to that of positive control boscalid (66.96%). Moreover, a hologram quantitative structure-activity relationship (HQSAR) model with good predictive capability was developed to provide in-depth insight into the activity profiles of these compounds. Preliminary mechanism studies suggested that compound 5r might exert its antifungal effect by changing hyphal morphology and increasing the membrane permeability. The present study contributes to the development of natural stilbene derivatives as alternative bioactive agents against B. cinerea.

Rational design, facile synthesis, and linear/nonlinear optical properties of novel two-photon absorption stilbene derivatives with different configurations

Four novel two-photon absorption compounds (1MOBI, 2MOHA, 3BrBI, and 4BrHA), which have assembled stilbene π-bridge, different electron acceptors and donors, were synthesized conveniently via the one-step Horner-Wadsworth-Emmons reaction. Their configurations are A-π-D-π-A, D′-π-D-π-D′, A′-π-A-π-A′, and D-π-A-π-D, respectively. Their linear and nonlinear optical properties including linear absorption, one-photon excited fluorescence, two-photon absorption, and two-photon excited fluorescence, were systematically investigated in various solvents. The results demonstrate that the compounds with dihexylamino donors exhibit good optical properties. 2MOHA and 4BrHA exhibit large two-photon absorption cross-sections (2183 and 1737 GM) in DMF, which are larger than those of many known stilbene derivatives. The relationships between the structures and the optical properties were studied aided with the time-dependent density functional theory calculations.

Tyrosinase Inhibitors from the Stems of Streblus Ilicifolius.

Two new stilbene derivatives, named strebluses C and D, were isolated from the EtOAc-soluble fraction of the stems of Streblus ilicifolius (Moraceae). Its absolute configuration was elucidated based on NMR spectroscopic data interpretation and optical rotation calculation. Streblus C possesses strong tyrosinase inhibitory activity with an IC50 value of 0.01 μM. Docking studies of 1 and 2 with oxy-tyrosinase were carried out to analyze their interactions. The analysis of the docked poses confirmed that 1 showed better binding affinity for oxy-tyrosinase than that of 2.

Aza-Peterson Olefinations: Rapid Synthesis of (E)-Alkenes

AbstractAn aza-Peterson olefination methodology to access 1,3-dienes and stilbene derivatives from the corresponding allyl- or benzyltrimethylsilane is described. Silanes can be deprotonated using Schlosser’s base and added to N-phenyl imines or ketones to directly give the desired products in high yields.

Stilbene Derivatives from the Leaves and Stems of Bletilla striata and their Cytotoxicity and Autophagy Activity

Stilbene Derivatives from the Leaves and Stems of Bletilla striata and their Cytotoxicity and Autophagy Activity

Borate transporters as models for studying SLC4 transport mechanisms

Borate transport proteins regulate the availability of borate, an essential plant micronutrient that is toxic in excess. Borate transporters share homology with SLC4 transporters, the archetypal member of which is human Band 3, or Anion Exchanger 1 (AE1). AE1 is the most abundant membrane protein in red blood cells where it exchanges bicarbonate and chloride, and mutations in AE1 are linked to several diseases. In this study we tested whether the S. cerevisiae Bor1 transporter (ScBor1) shares key features in common with the human AE1 transporter (HsAE1) to determine the extent to which ScBor1 serves as a relevant experimental model. Here we show evidence that, like HsAE1, ScBor1 is inhibited by the stilbene derivatives SITS and DIDS. Additionally, we demonstrate that the ScBor1 D347 residue, which is homologous to the essential E681 of HsAE1, can be complemented by the D347E but not D347N substitution. Lastly, we identify several new amino acids critical for function. These data collectively highlight similarities in the biochemical features of ScBor1 and HsAE1 and help elucidate their mechanisms.

The role of HCO3\u2013 in propionate-induced anion secretion across rat caecal epithelium

Propionate, a metabolite from the microbial fermentation of carbohydrates, evokes a release of epithelial acetylcholine in rat caecum resulting in an increase of short-circuit current (Isc) in Ussing chamber experiments. The present experiments were performed in order to characterize the ionic mechanisms underlying this response which has been thought to be due to Cl− secretion. As there are regional differences within the caecal epithelium, the experiments were conducted at oral and aboral rat corpus caeci. In both caecal segments, the propionate-induced Isc (IProp) was inhibited by > 85%, when the experiments were performed either in nominally Cl−- or nominally HCO3−-free buffer. In the case of Cl−, the dependency was restricted to the presence of Cl− in the serosal bath. Bumetanide, a blocker of the Na+-K+-2Cl−-cotransporter, only numerically reduced IProp suggesting that a large part of this current must be carried by an ion other than Cl−. In the aboral caecum, IProp was significantly inhibited by mucosally administered stilbene derivatives (SITS, DIDS, DNDS), which block anion exchangers. Serosal Na+-free buffer reduced IProp significantly in the oral (and numerically also in aboral) corpus caeci. RT-PCR experiments revealed the expression of several forms of Na+-dependent HCO3−-cotransporters in caecum, which might underlie the observed Na+ dependency. These results suggest that propionate sensing in caecum is coupled to HCO3– secretion, which functionally would stabilize luminal pH when the microbial fermentation leads to an increase in the concentration of short-chain fatty acids in the caecal lumen.

Carbazole-Cyanobenzene Dyes Electrografted to Carbon or Indium-Doped Tin Oxide Supports for Visible Light-Driven Photoanodes and Olefin Isomerizations.

The organic carbazole-cyanobenzene push-pull dye 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene was derivatized and attached to carbon or indium-doped tin oxide (ITO) electrodes by simple diazonium electrografting. The surface-bound dye is active and stable for the visible light photosynthetic isomerization of a wide range of functionalized stilbene and cinnamic acid derivatives. Up to 87,000 net turnovers were obtained for the isomerization of trans-stilbene. The isomerizations can be carried out in air with a 33% reduction in the rate. The ITO photoelectrodes are also active and stable toward photo-oxidations under basic and acidic conditions.

N‐Alkyl 3‐aminobut‐2‐enenitrile as a Non‐radioactive Side Product in Nucleophilic 18F‐Fluorination

AbstractWe found that acetonitrile acted as a reactant under the conventional reaction conditions for aliphatic nucleophilic 18F‐fluorination in acetonitrile to provide the N‐alkyl 3‐aminobut‐2‐enenitrile as one of the side products. Dimerization of acetonitrile promoted by a complex of K2CO3 and K222 provided 3‐aminobut‐2‐enenitrile, which acted as nucleophile to provide N‐alkyl amino derivatives. Based on the finding, avoiding acetonitrile in the drying of [18F]fluoride as well as 18F‐labeling enabled the preparation of 18F‐labeled compounds containing only a small amount of the corresponding alcohol. Finally, we used an automated synthesizer to achieve an efficient phase‐tag‐assisted synthesis of 18F‐labeled stilbene derivative as a 18F‐labeled amyloid‐β ligand.

First Total Synthesis of Gaylussacin and Its Stilbene Derivatives.

Gaylussacin (1), a stilbene glucoside, has been isolated from Pentarhizidium orientale and is used in Korean folk medicine. Although it was first isolated in 1972, the synthesis of gaylussacin has never been reported. Herein, we report the first total synthesis of gaylussacin in six steps with an overall yield of 23.8%, as well as the synthesis of its derivatives. Structurally, gaylussacin contains a carboxylic acid and a glycoside along with a free phenol on the same benzene ring, making selective functionalization for the synthesis of 1 difficult. Heck cross-coupling was employed as a key step to introduce the stilbene moiety. Glycosylation followed by global deprotection provided natural product 1.

(E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) induces cytoprotection in CCD18-Co human colon fibroblast cells through Nrf2/ARE pathway activation

Cytoprotection involving the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway is an important preventive strategy for normal cells against carcinogenesis. In our previous study, the chemopreventive potential of (E)-N-(2-(3, 5-Dimethoxystyryl) phenyl) furan-2-carboxamide (BK3C231) has been elucidated through its cytoprotective effects against DNA and mitochondrial damages in the human colon fibroblast CCD-18Co cell model. Therefore this study aimed to investigate the molecular mechanisms underlying BK3C231-induced cytoprotection and the involvement of the Nrf2/ARE pathway. The cells were pretreated with BK3C231 before exposure to carcinogen 4-nitroquinoline N-oxide (4NQO). BK3C231 increased the protein expression and activity of cytoprotective enzymes namely NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST) and heme oxygenase-1 (HO-1), as well as restoring the expression of glutamate-cysteine ligase catalytic subunit (GCLC) back to the basal level. Furthermore, dissociation of Nrf2 from its inhibitory protein, Keap1, and ARE promoter activity were upregulated in cells pretreated with BK3C231. Taken together, our findings suggest that BK3C231 exerts cytoprotection by activating the Nrf2 signaling pathway which leads to ARE-mediated upregulation of cytoprotective proteins. This study provides new mechanistic insights into BK3C231 chemopreventive activities and highlights the importance of stilbene derivatives upon development as a potential chemopreventive agent.

Chemical analysis and Biological properties of Terminalia macroptera Guill. & Perr. from Eastern Chad

Based on a previous ethnobotanical survey, <em>Terminalia macroptera</em> Guill. & Perr. was selected as its heartwood is traditionally used for infections treatment and as mosquito repellent in the province of Ouaddai (Chad). In our course for a better knowledge of this medicinal plant which could be developed as phytomedicine, it is of great interest to subsequently characterize the chemical profile and bioactivities of this plant. In the present study we develop an Ultrahigh-performance liquid chromatography with diode array detection coupled to electrospray ionization and quadrupole time-of-flight (UHPLC-DAD-ESI/QTOF) technique to characterized on line potentially bioactive compounds. Thirteen compounds were identified in active extracts and fractions from <em>Terminalia macroptera </em>Guill. & Perr. heartwood, namely gallic and ellagic acids derivatives, 23-<em>O</em>-galloyl-terminolic acid, 23-<em>O</em>-galloyl arjunolic acid, 4,4’-dihydroxy-Z-stilbene-<em>O</em>-rutinoside and 3,5,4’-trihydroxy-Z-stilbene-<em>O</em>-rutinoside. Antibacterial properties were evaluated against sensitive and resistant <em>Staphylococcus aureus</em> strains and antioxidant activities using 1,1-diphenyl-2-picryl-hydrazyl (DPPH). Stilbene derivatives, 23-<em>O</em>-galloyl-terminolic acid and 23-<em>O</em>-galloyl arjunolic acid are newly reported in <em>T. macroptera </em>Guill. & Perr.

Merging Whole‐cell Biosynthesis of Styrene and Transition‐metal Catalyzed Derivatization Reactions

AbstractThe approach of combining enzymatic and transition‐metal catalysis has been focused almost exclusively on using purified, isolated enzymes. The use of whole‐cell biocatalysis, instead of isolated enzymes, with transition‐metal catalysis, however, has been investigated only sparsely to date. Herein we present the development of two transition‐metal catalyzed reactions used to derivatize styrene obtained from whole‐cell biosynthesis. Using a biocompatible ruthenium cross‐metathesis catalyst up to 1.5 mM stilbene could be obtained in the presence of E. coli, which simultaneously produced styrene. Using palladium catalysts and arylboronic acids, titers of up to 1 mM of several stilbene derivatives were obtained. These two transition‐metal catalyzed reactions are valuable additions to the toolbox of combined whole‐cell biocatalysis and transition‐metal catalysis, offering the possibility to supplement biosynthetic pathways with the chemical versatility of abiological transition‐metal catalysis.

Nonlinear optical properties of diaromatic stilbene, butadiene and thiophene derivatives

Stilbene and butadiene derivatives display NLO activity with SHG intensities up to 32 times to that of urea for 2-chloro-3,4-dimethoxy-4′-nitrostilbene.