Stilbene Derivatives Research Articles

Design, synthesis, and biological evaluation of tetrahydroisoquinoline stilbene derivatives as potential antitumor candidates.

Herein, a novel class of tetrahydroisoquinoline stilbene derivatives were synthesized, and their potential in vitro anticancer activities were evaluated. Most of the compounds displayed inhibitory activity against one or more representative human cancer cell lines (lung cancer A549 cells, breast cancer MCF-7 cells, and human colorectal carcinoma HT-29 cells), especially compound 16e, which exhibited outstanding cytotoxicity to A549 cells. The tubulin polymerization assay demonstrated that compound 16e displayed better inhibition than colchicine when tested at the same concentration. It was found that 16e arrested A549 cells in G2/M phase by downregulating the expression of cell division cycle 2 (Cdc2) and upregulating the expression of proliferating cell nuclear antigen (PCNA) and cyclin B1. Flow cytometry and Western blot analysis indicated that 16e caused apoptosis via the mitochondrial-dependent apoptotic pathway by reducing mitochondrial membrane potential, inducing ROS accumulation, promoting the release of cytochrome C from the mitochondria into the cytoplasm, and further increasing the protein level of cleaved caspase-3. This work may inspire new ideas for the further improvement of tubulin-related anticancer drugs and treatments.

Isorhapontigenin ameliorates high glucose-induced podocyte and vascular endothelial cell injuries via mitigating oxidative stress and autophagy through the AMPK/Nrf2 pathway.

Diabetic nephropathy (DN) is a severe microvascular complication of diabetes mellitus and a primary reason for end-stage renal disease (ESRD). Isorhapontigenin (ISO), a natural derivative of stilbene, has significant anti-inflammatory and antioxidant effects. Nevertheless, its impact on DN remains elusive. Human vascular endothelial cells (HUVECs) and podocytes were damaged by high glucose (HG). Cell viability and apoptosis were testified by the cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. The mRNA profiles of antioxidant factors HO-1, NQO1, and Prx1 were monitored by real-time quantitative polymerase chain reaction (RT-qPCR). Western blotting (WB) was implemented to verify the expression of apoptosis-related proteins (Bax, Bad, and Bcl-XL), antioxidant factors (HO-1, NQO1, and Prx1), autophagy-related proteins (Beclin-1, ATG5, p62), podocalyxin (podocin, nephrin, and synaptopodin) and the AMPK/Nrf2 pathway. The levels of oxidative stress-related markers MDA, SOD and CAT were assessed with the corresponding kits. Compound C (CC), an inhibitor of AMPK, was deployed to probe the effects of modulating the AMPK/Nrf2 pathway on ISO in oxidative stress and autophagy in HUVECs and podocytes. Streptozotocin (STZ) was injected intraperitoneally into mice to establish an animal model of diabetes mellitus and to clarify the impact of ISO on the renal parameters such as serum creatinine, urea nitrogen and urinary protein in diabetic mice. ISO notably facilitated cell proliferation, impeded apoptosis, elevated the expression of antioxidant-related factors, alleviated HG-induced oxidative stress and activated autophagy in HUVECs and podocytes. ISO activated the AMPK/Nrf2 pathway. Attenuating AMPK diminished the protective effect of ISO on HUVECs and podocytes, curbed cell proliferation, intensified apoptosis and oxidative stress, and dampened autophagy. In-vivo experiments also displayed that ISO reduced histopathological damage, lowered serum creatinine, urea nitrogen and urinary ACR levels, and eased kidney damage in DN mice. ISO attenuates HG-induced oxidative stress and activates autophagy by motivating the AMPK/Nrf2 pathway, exerting a protective effect on HUVECs and podocytes and reducing renal injury in DN mice.

Computational search for radical-bearing stilbene derivatives with switchable magnetic properties

Computational search for radical-bearing stilbene derivatives with switchable magnetic properties

Thiazoles: A Retrospective Study on Synthesis, Structure-activity Relationship and Therapeutic Significance

Abstract: Thiazole or 1,3-thiazole is a distinct heterocyclic compound which incorporates sulphur and nitrogen atoms. It is a vital framework present in numerous pharmacologically active compounds, be it of natural origin or of synthetic nature. Many thiazoles having antitumor and antiviral activities, originate from microbes and marine organisms. A variety of synthetic drugs, having thiazole group, like antimicrobial sulfathiazole, antibiotic penicillin, antidepressant pramipexole, antineoplastic agent bleomycin, antiretroviral drug ritonavir, histamine H2 receptor antagonist nizatidine, anti-inflammatory drug meloxicam, antifungal stilbene derivatives have been in the markets for quite some time. Hofmann and Hantzsch laid the groundwork for further development in the field of thiazole chemistry. The interaction of α-haloketones or α-halogenaldehyde and thioamide to obtain thiazoles is beautifully described by Hantzsch. Various studies have reported methods for the synthesis of the thiazoles; thioforamide, thiourea, α-thiocyanotoketones, and vinyl bromide have been extensively employed to synthesize thiazoles. The thiazoles have immense potential and this study tries to enlighten the crucial role of thiazoles for the betterment of society. The review provides different directions in the synthesis of novel thiazoles and also reveals diverse targets for augmentation in the field of designing of novel thiazoles. Keywords: Thiazoles, Synthesis, QSAR, Molecular Docking, Biological Activity

Trans-ferulic acid valorization into stilbene derivatives via tandem decarboxylation/Heck coupling using Pd/Al-SBA-15 materials

Pd-containing Al-SBA-15 materials were prepared and characterized in view of their utilization in the two-step valorization of trans-ferulic acid into stilbenes via tandem decarboxylation/Mizoroki-Heck coupling. Materials were found to be highly active and selective in the proposed chemistries, with quantitative conversion to target products under mild reaction conditions (typically 100 °C, 3–6 h reaction). Relevant insights on catalyst deactivation via sintering (Pd nanoparticles agglomeration) were also observed for the synthesized materials.

Fungal Degradation of Extractives Plays an Important Role in the Brown Rot Decay of Scots Pine Heartwood.

Scots pine heartwood is known to have resistance to wood decay due to the presence of extractives, namely stilbenes and resin acids. However, previous studies have indicated that these extractives are degradable by wood decaying fungi. This study aimed to investigate the relationship between extractive degradation and heartwood decay in detail and to gain insight into the mechanisms of extractive degradation. Mass losses recorded after a stacked-sample decay test with brown rot fungi showed that the heartwood had substantial decay resistance against Coniophora puteana but little resistance against Rhodonia placenta. Extracts obtained from the decayed heartwood samples revealed extensive degradation of stilbenes by R. placenta in the early stages of decay and a noticeable but statistically insignificant loss of resin acids. The extracts from R. placenta-degraded samples contained new compounds derived from the degraded extractives: hydroxylated stilbene derivatives appeared in the early decay stages and then disappeared, while compounds tentatively identified as hydroxylated derivatives of dehydroabietic acid accumulated in the later stages. The degradation of extractives was further analysed using simple degradation assays where an extract obtained from intact heartwood was incubated with fungal mycelium or extracellular culture fluid from liquid fungal cultures or with neat Fenton reagent. The assays showed that extractives can be eliminated by several fungal degradative systems and revealed differences between the degradative abilities of the two fungi. The results of the study indicate that extractive degradation plays an important role in heartwood decay and highlight the complexity of the fungal degradative systems.

A stilbene derivative as dual-channel fluorescent probe for mitochondrial G-quadruplex DNA in living cells

G-quadruplex DNA has attracted the widespread attention as a novel target of anticancer strategy. Herein, two novel stilbene derivatives 2a and 2b were designed and synthesized under mild reaction conditions, and their interactions with G-quadruplex DNA, cytotoxicity, and distribution in living cells were investigated in detail. Both compounds display a low cytotoxicity and the higher affinity to G-quadruplex DNA than to the other secondary structures, including duplex, single-stranded and i-motif DNA, moreover, the affinity of 2b with m-allyl pyridine salt group to G-quadruplex DNA is about 10-fold stronger than that of 2a with p-allyl pyridine salt group. The interactions of the compounds with the promoter G-quadruplexes are enthalpy-driven by an ITC assay. 2a and 2b not only stabilize the G-quadruplex structure but also induce the G-rich sequences (bcl-2, HRCC and KSS) to fold into the mixed-type G-quadruplex in Na+/K+ free Tris-HCl buffer at pH 7.0, and 2b presents the higher stabilization to G-quadruplex than 2a by a FRET-melting assay. 2b presents a dual-emission at 508 and 600 nm and gives a turn-on and stronger and more sensitive fluorescence response over 2a to the promoter (bcl-2, c-kit 2 and c-myc) and mitochondrial (HRCC and KSS) G-quadruplex DNA at both emission wavelengths, moreover, the peak at 508 nm is blue-shifted to 466 nm after binding to DNA. The blue and red dual-channel CLSM images indicate that 2b is mainly distributed in the mitochondrion of living HepG2 cells. The results show that 2b is a potential dual-channel fluorescent probe for mitochondrial G-quadruplex DNA in living cells.

Chemoenzymatic Synthesis of Original Stilbene Dimers Possessing Wnt Inhibition Activity in Triple-Negative Breast Cancer Cells Using the Enzymatic Secretome of Botrytis cinerea Pers.

The Wnt signaling pathway controls multiple events during embryonic development of multicellular animals and is carcinogenic when aberrantly activated in adults. Breast cancer and triple-negative breast cancer (TNBC) in particular depend upon Wnt pathway overactivation. Despite this importance, no Wnt pathway-targeting drugs are currently available, which necessitates novel approaches to search for therapeutically relevant compounds targeting this oncogenic pathway. Stilbene analogs represent an under-explored field of therapeutic natural products research. In the present work, a library of complex stilbene derivatives was obtained through biotransformation of a mixture of resveratrol and pterostilbene using the enzymatic secretome of Botrytis cinerea. To improve the chemodiversity, the reactions were performed using i-PrOH, n-BuOH, i-BuOH, EtOH, or MeOH as cosolvents. Using this strategy, a series of 73 unusual derivatives was generated distributed among 6 scaffolds; 55 derivatives represent novel compounds. The structure of each compound isolated was determined by nuclear magnetic resonance and high-resolution mass spectrometry. The inhibitory activity of the isolated compounds against the oncogenic Wnt pathway was comprehensively quantified and correlated with their capacity to inhibit the growth of the cancer cells, leading to insights into structure-activity relationships of the derivatives. Finally, we have dissected mechanistic details of the stilbene derivatives activity within the pathway.

An effective combination of reusable Pd@MOF catalyst and deep eutectic solvents for high-performance C–C coupling reaction

Pd-incorporated Zr-based metal–organic framework containing sulfone groups, named Pd(II)BUT-11, was successfully prepared by dispersing the sulfone-functionalized MOF in Pd(OAc)2 solution. X-ray diffraction, scanning electron microscopy, N2 isotherm sorption, X-ray photoelectron spectroscopy, and thermogravimetric analysis were applied to determine the features of the Pd-incorporated MOF. In the catalytic studies, Pd(II)@BUT-11 was shown to be an efficient heterogeneous catalyst for synthesizing various stilbene derivatives via the cross-coupling Heck reaction with DABCO-derived deep eutectic solvent (DES) as a green solvent. Notably, the catalyst and the solvent could be recovered and reused, with their activity and structure remaining stable throughout several trials. The method provides an alternative solution to the conventional catalysts and solvents, resulting in a green and efficient stilbene synthesis process. Furthermore, the stilbenes were separated by extraction with ethyl acetate due to the low solubility of DES with this solvent.

Unraveling a role of molecular linker in nanoparticles self-organization by SERS spectroscopy: Comparative study of three aromatic diamines

The preparation of controllable small noble metal nanoparticle (NP) aggregates is required for plasmon-enhanced spectroscopy and metamaterials development. In this work, we present a systematic study of three aromatic diamines as possible linkers of silver NPs. Symmetric 4,4′-derivatives of bibenzyl, stilbene and tolane have been selected to reveal the effect of linker rigidity and conjugation degree on the morphology and optical properties of the obtained aggregates. Surface-enhanced Raman scattering spectra of colloidal solutions with different aromatic amine additives have been acquired to assess the surface equilibria and adsorbate state. The non-monotonic concentration profiles have been obtained in the case of effective NPs linking and can be considered as its feature. Transmission electron microscopy and absorption spectroscopy have been involved for the analysis of size and morphology of NPs aggregates. Effective linking of silver NPs is established for stilbene and tolane compounds, which give quasi-spherical aggregates and elongated dimers/trimers. Surface-initiated azo conversion is revealed for bibenzyl compound instead of NPs bridging. The tendency to decrease the degree of NP aggregation with increasing aromaticity and “springiness” of molecular linker is observed. The capability of rigid diamines to assemble the nanoparticles with a finite degree of aggregation, even at high concentrations, distinguishes them advantageously from aliphatic bifunctional linkers. Highly stable plasmonic aggregates can be obtained in this way and implemented further as building blocks for nano- and meta-materials, as well as for tags in imaging applications.

Discovery of a Novel Stilbene Derivative as a Microtubule Targeting Agent Capable of Inducing Cell Ferroptosis.

Microtubule targeting agents (MTAs) are used as clinically effective chemotherapies for cancer treatment but might be limited by the acquired or intrinsic resistance of cancer cells to apoptosis. The vulnerability of therapy-resistant cancers to ferroptosis provides an alternative way to overcome drug resistance. In this study, on the basis of the MTAs obtained in our previous studies, a series of MTAs were synthesized, and detailed structure-activity relationships were obtained through extensive molecular dynamics studies. Among them, a diphenylethene derivative, compound 33, displayed the most potent activity in vitro and in vivo, with IC50 values of 10-50 nM toward six cancer cell lines and a 78.6% tumor growth inhibition in vivo. Interestingly, although it acted as the MTA, compound 33 triggered cell death mainly through cell ferroptosis rather than apoptosis, which might provide an alternative way to eradicate apoptosis-related drug resistance.

The Mizoroki‐Heck Reaction in Tunable Aryl Alkyl Ionic Liquids

AbstractWe report the use of imidazolium based tunable aryl alkyl ionic liquids (TAAILs) as solvents in the Mizoroki–Heck reaction. Different commercially available palladium sources, inorganic bases, TAAILs and reaction conditions were tested for the synthesis of trans‐stilbene using bromobenzene and styrene. A variety of different stilbene derivatives were synthesized with exclusive formation of the (E)‐isomers and isolated yields up to 97 %. We were able to optimize the reaction conditions using only 0.25 mol% of Pd(OAc)2 as the catalyst and a reaction time of 4 hours. No additional ligands or additives are used in the reaction. The catalytic system using TAAILs achieved higher yields than commercially available imidazolium and phosphonium ionic liquids, demonstrating the potential of tailored ionic liquids as a reaction medium for the Mizoroki–Heck reaction.

Selective Encapsulation and Unusual Stabilization of cis-Isomers by a Spherical Polyaromatic Cavity.

To explore new cavity functions, we herein employed cis-trans stereoisomers with a N=N, C=C, or C=N unit as guest indicators for a polyaromatic capsule. Thanks to the rigid, spherical cavity with a diameter of ∼1 nm, azobenzene and stilbene derivatives are quantitatively encapsulated by the capsule with 100 % cis-selectivity in water. The isomerization of the cis-azo compound is suppressed against heat and light in the cavity, due to the confinement effect. Furthermore, C,N-diphenyl imine derivatives are quantitatively encapsulated by the capsule in water and adopt an otherwise unstable cis-form. The polyaromatic cavity suppresses the hydrolysis of the imines in water, even at elevated temperature, due to the shielding effect. Accordingly, the properties of the cis-trans isomers could be largely altered through supramolecular manipulation.

Molecular dynamics simulations, docking and MMGBSA studies of newly designed peptide-conjugated glucosyloxy stilbene derivatives with tumor cell receptors.

In this work, for the first time, we designed derivatives of beta-D-glucosyloxy-3-hydroxy-trans-stiblene-2-carboxylic acid (GHS), by conjugating GHS with tumor targeting peptides RPARPAR and GGKRPAR to target over-expressed receptors in tumor cells. The sequences RPARPAR and GGKRPAR are known to target the neuropilin1 (NRP1) receptor due to the C-terminal Arg domain; however, their effectiveness has never been examined with other commonly over-expressed receptors in tumor cells, particularly of chronic lymphocytic leukemia that include integrin α1β1 and CD22. By conjugating these peptides with GHS, which is known for its inherent anti-cancer properties, the goal is to further enhance tumor cell targeting by developing compounds that can target multiple receptors. The physicochemical properties of the conjugates and individual peptides were analyzed using Turbomole and COSMOthermX20 in order to determine their hydrogen bond accepting and donating capabilities. The web server POCASA was used in order to determine the surface cavities and binding pockets of the three receptors. To explore the binding affinities, we conducted molecular docking studies with the peptides and the conjugates with each of the receptors. After molecular docking, the complexes were analyzed using Protein-Ligand Interaction Profiler to determine the types of interactions involved. Molecular dynamics simulation studies were conducted to explore the stability of the receptor-ligand complexes. Our results indicated that in most cases the conjugates showed higher binding and stability with the receptors. Additionally, highly stable complexes of conjugates were obtained with CD22, NRP1 and in most cases with the integrin α1β1 receptor as well. The binding energies were calculated for each of the receptor ligand complexes through trajectory analysis using MMGBSA studies. SwissADME studies revealed that the compounds showed low GI absorption and were not found to be CYP inhibitors and had bioavailability score that would allow them to be considered as potential drug candidates. Overall, our results for the first time show that the designed conjugates can target multiple over-expressed receptors in tumor cells and may be potentially developed as future therapeutics for targeting tumor cells.

Heterocyclic Stilbene and Bibenzyl Derivatives in Liverworts: Distribution, Structures, Total Synthesis and Biological Activity

Heterocyclic Stilbene and Bibenzyl Derivatives in Liverworts: Distribution, Structures, Total Synthesis and Biological Activity

Six Undescribed Derivatives of Stilbene Isolated from Lindera Reflexa Hemsl. And Their Anti-Tumor and Anti-Inflammatory Activities

Six Undescribed Derivatives of Stilbene Isolated from Lindera Reflexa Hemsl. And Their Anti-Tumor and Anti-Inflammatory Activities

Amphiphilic stilbene derivatives attenuate the neurotoxicity of soluble Aβ42 oligomers by controlling their interactions with cell membranes.

The misfolded proteins or polypeptides commonly observed in neurodegenerative diseases, including Alzheimer's disease (AD), are promising drug targets for developing therapeutic agents. To target the amyloid-β (Aβ) peptide plaques and oligomers, the hallmarks of AD, we have developed twelve amphiphilic small molecules with different hydrophobic and hydrophilic fragments. In vitro fluorescence binding assays demonstrate that these amphiphilic compounds show high binding affinity to both Aβ plaques and oligomers, and six of them exhibit selective binding toward Aβ oligomers. These amphiphilic compounds can also label the Aβ species in the brain sections of transgenic AD mice, as shown by immunostaining with an Aβ antibody. Molecular docking studies were performed to obtain structure-affinity relationships. To our delight, four amphiphilic compounds can alleviate the Cu2+-Aβ induced toxicity in cell viability assays. In addition, confocal fluorescence imaging studies provide evidence that two compounds, ZY-15-MT and ZY-15-OMe, can disrupt the interactions between Aβ oligomers and human neuroblastoma SH-SY5Y cell membranes. Overall, these studies strongly suggest that developing compounds with amphiphilic properties that target Aβ oligomers and modulate the Aβ oligomer-cell membrane interactions can be an effective strategy for the development of small molecule AD therapeutics.

Insights into the Effect of Trans-to-Cis Photoisomerization of a Co-coordinated Stilbene Derivative on the Luminescence of Di-β-diketonate Lanthanide Complexes.

Five lanthanide complexes constructed from a stilbene derivative, (E)-N′,N′-bis(pyridin-2-ylmethyl)-4-styrylbenzoyl hydrazide (HL), and two β-diketonates (2-thenoyltrifluoroacetonate, tta), with or without a trifluoroacetate anion (CF3CO2–), namely, [Ln(tta)2(HL) (CF3CO2)] [LnC45H32F9N4O7S2, Ln = La (1), Nd (2), Eu (3), or Gd (4)] and [Yb(tta)2(L)] (YbC43H31F6N4O5S2 (5), L = deprotonated HL), were synthesized and characterized. Crystals of these five complexes were obtained and analyzed by single-crystal X-ray diffraction. These complexes all belonged to the monoclinic P21/c space group. For La3+, Nd3+, Eu3+, and Gd3+, the central lanthanide ion was nine-coordinate with a monocapped twisted square antiprism polyhedron geometry. The central Yb3+ ion of complex 5 was eight-coordinate with a distorted double-capped triangular prism polyhedron geometry. Among the five complexes, trans-to-cis photoisomerization of the stilbene group in gadolinium complex 4 showed the largest quantum yield. Complexes 2, 3, and 4 showed dual luminescence and photoisomerization functions. The luminescence change of complex 3 was reversible upon the trans-to-cis photoisomerization process. The sensitization efficiencies of luminescent europium complex 3 in acetonitrile solutions and in the solid state were 49.9 and 42.6%, respectively. These medium sensitization efficiencies led to the observation of simultaneous photoisomerization and luminescence, which further confirmed our previous report that photoisomerization of the stilbene group within complexes was related to the lanthanide ion energy level and whether a ligand-to-metal center or ligand-to-ligand charge-transfer process was present. In complexes 1–5, in addition to the intramolecular absorption transition of the ligand itself (IL, πHL–πHL* and πtta–πtta*), the presence of a ligand-to-ligand charge-transfer transition between tta and HL (LLCT, πtta–πHL* or πHL–πtta*) indicated whether the triplet-state energy of HL was able to transfer to the excited energy level of the lanthanide ions, leading to different extents of HL photoisomerization. These results provide an important route for the design of new dual-function lanthanide-based optical switching materials.

Antioxidant activity and nano delivery of the most frequently applied stilbene derivatives: A brief and recent review

As of recent, the appearance rate of several degenerative diseases and cancer influenced by oxidative stress continues to increase dramatically. Many compounds with high potential antioxidant activity have been explored and used extensively, i.e., as preventive or curative treatments. Stilbene and its derivates have high potential antioxidant activity contained in several botanical sources. To date, source exploration and antioxidant activity study of stilbene derivate has been reported. However, the nano-delivery of stilbene derivate meant to increase the antioxidant activity and stability is still a limited process. This review is devoted to brief and recent outlooks regarding the antioxidant activity and delivery system of the most frequently applied stilbene and its derivates, namely resveratrol and pterostilbene.

Natural products isolation studies of the paleoendemic plant species Nothofagus gunnii and Nothofagus cunninghamii

The first natural product isolation studies of Nothofagus gunnii (Hook.f.) Oerst and Nothofagus cunninghamii (Hook.f.) Oerst have been undertaken. A previously unreported stilbene derivative, pinosylvin monoacetate, was isolated from the leaves of N. gunnii, in addition to 14 known compounds; including the flavonoids galangin, pinobanksin, catechin and quercetin; sesquiterpenoids such as, ilicol and (+)-β-costol acetate; 2,4-dihydroxy-6-methoxychalcone and pinosylvin. Four known flavonoid natural products, catechin, quercetin, ayanin, and avicularin were isolated from the leaves of N. cunninghamii. This study reveals that N. gunnii is a rich source of flavonoid, chalcone and stilbene compounds, while primarily hydroxyflavonoid compounds are found in N. cunninghamii. The isolated phytochemicals are consistent with the evolutionary relationships suggested to exist among Nothofagus species.