Prenylated Stilbenoids Affect Inflammation by Inhibiting the NF-κB/AP-1 Signaling Pathway and Cyclooxygenases and Lipoxygenase.

Stilbenoids are important components of foods (e.g., peanuts, grapes, various edible berries), beverages (wine, white tea), and medicinal plants. Many publications have described the anti-inflammatory potential of stilbenoids, including the widely known trans-resveratrol and its analogues. However, comparatively little information is available regarding the activity of their prenylated derivatives. One new prenylated stilbenoid (2) was isolated from Artocarpus altilis and characterized structurally based on 1D and 2D NMR analysis and HRMS. Three other prenylated stilbenoids were prepared synthetically (9-11). Their antiphlogistic potential was determined by testing them together with known natural prenylated stilbenoids from Macaranga siamensis and Artocarpus heterophyllus in both cell-free and cell assays. The inhibition of 5-lipoxygenase (5-LOX) was also shown by simulated molecular docking for the most active stilbenoids in order to elucidate the mode of interaction between these compounds and the enzyme. Their effects on the pro-inflammatory nuclear factor-κB (NF-κB) and the activator protein 1 (AP-1) signaling pathway were also analyzed. The THP1-XBlue-MD2-CD14 cell line was used as a model for determining their anti-inflammatory potential, and lipopolysaccharide (LPS) stimulation of Toll-like receptor 4 induced a signaling cascade leading to the activation of NF-κB/AP-1. The ability of prenylated stilbenoids to attenuate the production of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) was further evaluated using LPS-stimulated THP-1 macrophages.

Sterols from Thai Marine Sponge Petrosia (Strongylophora) sp. and Their Cytotoxicity.

Eight new sterols (1-5 and 11-13), together with eight known compounds (6-10 and 14-16) were isolated from marine sponge Petrosia sp. The structures of these compounds were elucidated on the basis of extensive spectroscopic analysis. The cytotoxicity of some compounds against a panel of human cancer cell lines is also reported.

Superbanone, A New 2-Aryl-3-benzofuranone and Other Bioactive Constituents from the Tube Roots of Butea superba.

Phytochemical investigation from the tube roots of Butea superba, led to the isolation and identification of a new 2-aryl-3-benzofuranone named superbanone (1), one benzoin, 2-hydroxy-1-(2-hydroxy-4-methoxyphenyl)-2-(4-methoxyphenyl)ethanone (2), eight pterocarpans (3 - 10), and eleven isoflavonoids (11 - 21). Compound 2 was identified for the first time as a natural product. The structure of the isolated compounds was elucidated using spectroscopic methods, mainly 1D- and 2D-NMR. The isolated compounds and their derivatives were evaluated for α-glucosidase inhibitory and antimalarial activities. Compounds 3, 7, 8, and 11 showed promising α-glucosidase inhibitory activity (IC50  = 13.71 ± 0.54, 23.54 ± 0.75, 28.83 ± 1.02, and 12.35 ± 0.36 µm, respectively). Compounds 3 and 11 were twofold less active than the standard drug acarbose (IC50  = 6.54 ± 0.04 µm). None of the tested compounds was found to be active against Plasmodium falciparum strain 94. On the basis of biological activity results, structure-activity relationships are discussed.

α-Glucosidase inhibitory activities of isoflavanones, isoflavones, and pterocarpans from Mucuna pruriens.

Three new isoflavanones (1-3) and thirteen known compounds (4-16) were isolated from the roots of Mucuna pruriens. The absolute configurations of isoflavanones 1-3 and parvisoflavanone (4), lespedeol C (5), and uncinanone C (6) were addressed by a circular dichroism technique. Isoflavanones, isoflavones, and pterocarpans of M. pruriens were found to be α-glucosidase inhibitors. Medicarpin (7) and parvisoflavone B (9) were potent α-glucosidase inhibitors (twofold less active than the standard drug acarbose). The production of bioactive metabolites in M. pruriens seems to be season-dependent.

Grewiifopenes A-K, bioactive clerodane diterpenoids from Casearia grewiifolia Vent.

Eleven novel clerodane-type diterpenoids, grewiifopenes A-K (1-4 and 12-18), along with nine known compounds (5-11, 19, and 20) were purified from the dichloromethane extract of the twigs and stems of Casearia grewiifolia Vent. (Salicaceae). Their spectroscopic data, including the NMR, HRESIMS, and electronic circular dichroism calculations were employed to completely characterize and elucidate the chemical structures and absolute configurations. The clerodane diterpenoids possessing a 6-OH group and no substitution at C-7 exhibited greater cytotoxic activity than others, with their IC50 values ranging from 0.3 to 2.9 µM. Isocaseamembrin E (7) exhibited antibacterial activity against Staphylococcus aureus, while isocaseamembrin E (7), corymbulosin X (8), caseargrewiin A (9), kurzipene A (10), and balanspene F (11) exhibited antibacterial activity against Bacillus cereus.

Enhancing Solubility and Bioefficacy of Stilbenes by Liposomal Encapsulation-The Case of Macasiamenene F.

Stilbenes in food and medicinal plants have been described as potent antiphlogistic and antioxidant compounds, and therefore, they present an interesting potential for the development of dietary supplements. Among them, macasiamenene F (MF) has recently been shown to be an effective anti-inflammatory and cytoprotective agent that dampens peripheral and CNS inflammation in vitro. Nevertheless, this promising molecule, like other stilbenes and a large percentage of drugs under development, faces poor water solubility, which results in trickier in vivo administration and low bioavailability. With the aim of improving MF solubility and developing a form optimized for in vivo administration, eight types of conventional liposomal nanocarriers and one type of PEGylated liposomes were formulated and characterized. In order to select the appropriate form of MF encapsulation, the safety of MF liposomal formulations was evaluated on THP-1 and THP-1-XBlue-MD2-CD14 monocytes, BV-2 microglia, and primary cortical neurons in culture. Furthermore, the cellular uptake of liposomes and the effect of encapsulation on MF anti-inflammatory effectiveness were evaluated on THP-1-XBlue-MD2-CD14 monocytes and BV-2 microglia. MF (5 mol %) encapsulated in PEGylated liposomes with an average size of 160 nm and polydispersity index of 0.122 was stable, safe, and the most promising form of MF encapsulation keeping its cytoprotective and anti-inflammatory properties.

Dulcisenes C-E, polyoxygenated cyclohexenes, from Uvaria dulcis dunal and their cytotoxic activity.

Dulcisenes C-E, undescribed polyoxygenated cyclohexenes and twenty-one known compounds were isolated from the dichloromethane extract of the leaves of Uvaria dulcis Dunal. The structures of these undescribed compounds were determined by spectroscopic data analyses, including 1D and 2D NMR, IR, and MS techniques; their absolute configurations were analyzed by NOESY and ECD spectra. Cytotoxicity of sixteen more abundant isolates was evaluated. Cherrevenone and 2',3'-dihydroxy-4',6'-dimethoxychalcone exhibited cytotoxic activity against some cancer cell lines with IC50 values in the range of 3.3-11.8 µM.

Glutarimide alkaloids and a terpenoid benzoquinone from Cordia globifera.

Three new compounds, a meroterpene (2) having a cyclopropane moiety named globiferane and glutarimide alkaloids named cordiarimides A (3) and B (4), were isolated from the roots of Cordia globifera. Compounds 2-4 exhibited weak cytotoxic activity. Cordiarimide B (4) exhibited radical scavenging activity, as it inhibited superoxide anion radical formation in the xanthine/xanthine oxidase (XXO) assay, and also suppressed superoxide anion generation in differentiated HL-60 human promyelocytic leukemia cells when induced by 12-O-tetradecanoylphorbol-13-acetate (TPA). This is the first report on the presence of glutarimide alkaloids in the genus Cordia.

Atalantiaphyllines A-G, prenylated acridones from Atalantia monophylla DC. and their aromatase inhibition and cytotoxic activities.

Seven previously undescribed acridones, named atalantiaphyllines A-G, along with twenty-six known compounds were isolated from the dichloromethane extracts of roots and stems of Atalantia monophylla DC. Their structures were elucidated by analysis of extensive NMR and HRMS data. Aromatase inhibition, cytotoxicity against MOLT-3, HepG2, A549 and HuCCA-1 cell lines and DPPH radical scavenging activity of these compounds were evaluated. Most of the tested acridones exhibited higher potency in inhibiting aromatase than the positive control, ketoconazole, with IC50 values in the range of 0.08-2.0 µM. In the cytotoxicity assay, cycloataphylline A, N-methylbuxifoliadine E and atalantiaphylline G were selectively cytotoxic against MOLT-3 cell line with IC50 values of 8.0, 5.4 and 9.8 µM, respectively, while only atalaphyllidine exhibited highest antioxidant activity as evaluated by DPPH free radical scavenging assay with an IC50 value of 22.4 µM.

Therapeutic potential of prenylated stilbenoid macasiamenene F through its anti-inflammatory and cytoprotective effects on LPS-challenged monocytes and microglia.

ETHNOPHARMACOLOGICAL RELEVANCE: Macaranga Thou. (Euphorbiaceae) is a large genus that comprises over 300 species distributed between Western Africa and the islands of the South Pacific. Plants of this genus have a long-standing history of use in traditional medicine for different purposes, including the treatment of inflammation. Fresh and dried leaves of certain Macaranga species (e.g. M. tanarius (L.) Müll.Arg.), have been used to treat cuts, bruises, boils, swellings, sores and covering of wounds in general. Several reports described Macaranga spp. being a rich source of polyphenols, such as prenylated stilbenoids and flavonoids, mostly responsible for its biological activity. Similarly, an abundant content of prenylated stilbenes was also described in M. siamensis S.J.Davies, species recently identified (2001) in Thailand. While the respective biological activity of the prenylated stilbenes from M. siamensis was poorly investigated to date, our recent study pointed out the interest as the natural source of several novel anti-inflammatory stilbenoids isolated from this species. AIM OF THE STUDY: This work investigated the potential anti-inflammatory effects of the stilbenoid macasiamenene F (MF) isolated from M. siamensis S.J.Davies (Euphorbiaceae) on the lipopolysaccharide (LPS)-induced inflammation-like response of monocytes and microglia, major cells involved in the peripheral and central inflammatory response, respectively. MATERIALS AND METHODS: LPS-induced stimulation of TLR4 signaling led to the activation of inflammatory pathways in in vitro models of THP-1 and THP-1-XBlue™-MD2-CD14 human monocytes, BV-2 mouse microglia, and an ex vivo model of brain-sorted mouse microglia. The ability of the stilbenoid MF to intervene in the IкB/NF-кB and MAPKs/AP-1 inflammatory cascade was investigated. The gene and protein expressions of the pro-inflammatory cytokines IL-1ß and TNF-α were evaluated at the transcription and translation levels. The protective effect of MF against LPS-triggered microglial loss was assessed by cell counting and the LDH assay. RESULTS: MF demonstrated beneficial effects, reducing both monocyte and microglial inflammation as assessed in vitro. It efficiently inhibited the degradation of IкBα, thereby reducing the NF-кB activity and TNF-α expression in human monocytes. Furthermore, the LPS-induced expression of IL-1ß and TNF-α in microglia was dampened by pre-, co-, or post-treatment with MF. In addition to its anti-inflammatory effect, MF demonstrated a cytoprotective effect against the LPS-induced death of BV-2 microglia. CONCLUSION: Our research into anti-inflammatory and protective effects of MF has shown that it is a promising candidate for further in vitro and in vivo investigations of MF interventions with respect to acute and chronic inflammation, including potentially beneficial effects on the inflammatory component of brain diseases such as stroke and Alzheimer's disease.

Diverse flavonoids from the roots of Millettia brandisiana.

The phytochemical investigation for the constituents of the roots of Millettia brandisiana, using bioassay guided fractionation, resulted in the isolation of five previously undescribed (namely brandisianones A-E) and twenty-six known flavonoids. Their chemical structures were determined using a combination of NMR, MS, IR, optical rotation and CD analysis, as well as comparison with the literature data. The crude extract as well as the isolated compounds were evaluated in various biological assays for their cytotoxicity against a panel of human cancer cell lines, potential inhibitory activity against aromatase, and antioxidant property using the oxygen radical absorbance capacity (ORAC) with an aim to search for leads and develop them to drug candidates in our drug discovery effort, we identified three bioactive flavonoids from M. brandisiana which could be further developed into a potential chemopreventive (antiaromatase) agent against breast cancer.

Pyranocoumarins from the twigs of Mammea siamensis.

Four unusual pyranocoumarins (1-4) have been isolated from the dried twigs of M. siamensis. The structures were determined by spectroscopic data, especially 1D and 2D NMR experiments.

Siamenols A-D, four new coumarins from Mammea siamensis.

Further investigation of the dichloromethane extract of the twigs of Mammea siamensis led to the isolation of four novel coumarins, named siamenols A-D (1-4) together with three known xanthones. The structures of the new coumarins were elucidated by spectroscopic analysis, including 2D NMR spectroscopic data. In addition, the absolute stereochemistry of hydroxyl group of siamenol C (3) was determined to be S configuration by using modified Mosher's method.

Cytotoxic sesquiterpenes from the endophytic fungus Pseudolagarobasidium acaciicola.

Twenty previously unknown compounds and two known metabolites, merulin A and merulin D, were isolated from the endophytic fungus Pseudolagarobasidium acaciicola, which was isolated from a mangrove tree, Bruguiera gymnorrhiza. Structures of the 20 compounds were elucidated by analysis of spectroscopic data. The absolute configuration of seven of these compounds was addressed by a single crystal X-ray analysis using CuKα radiation and an estimate of the Flack parameter. Three compounds also possessed a tricyclic ring system. Terpene endoperoxides isolated exhibited cytotoxic activity, while those without an endoperoxide moiety did not show activity. The endoperoxide moiety of sesquiterpenes has significant impact on cytotoxic activity, and thus is an important functionality for cytotoxicity. One terpene endoperoxide displayed potent cytotoxic activity (IC50 0.28µM), and selectively exhibited activity against the HL-60 cell line.

Bioactive cardinane sesquiterpenes from the stems of Alangium salviifolium.

A dichloromethane extract of the stems of Alangium salviifolium afforded twelve cardinane sesquiterpenes, seven of which are new alangenes A-G (1-7) and five known compounds (8-12). Their structures were elucidated on the basis of spectroscopic techniques including UV, IR, and NMR spectroscopies, and mass spectrometry. Most of the tested compounds exhibited very potent aromatase inhibition properties, especially in the case of the cardinane sesquiterpenes 1, 5-8, and 10 (IC50 values of 0.09, 0.13, 0.30, 0.06, 2.05, and 1.19 µM, respectively), which are significantly better than that of the positive control (ketoconazole, IC50 of 2.4 µM). Compounds 1 and 4 exhibited selective cytotoxicity against the MOLT-3 cancer cell line with IC50 values of 7.9 and 2.1 µg mL(-1) , respectively.

Terpenoids from the roots of Drypetes hoaensis and their cytotoxic activities.

Seven terpenoids consisting of five sesquiterpenoids, hoaensieremone, hoaensieremodione, hoaensifuranonal, hoaensieudesone, and hoaensibenzofuranal, and two friedelane triterpenoids, 3α-(E)-p-coumaroyloxyfriedelan-7-one and 3α-(E)-caffeoyloxyfriedelan-7-one were isolated from the dichloromethane extract of the roots of Drypetes hoaensis. Additionally, twelve known compounds and vanillin were isolated. Their structures were established on the basis of spectroscopic analysis, as well as by comparison with literature data. The anticancer activity of nine of these compounds was investigated.

5-formylfurfuryl esters from Duabanga grandiflora.

5-Formylfurfuryl esters, duabanganals A-D, together with sixteen known compounds, a known 5-formylfurfuryl ester, latifolinal, eight pentacyclic triterpenes, a benzofuran derivative, an ellagic acid derivative, vanillin, ß-sitosterol, ß-sitosterol glucoside, 3-hydroxy-4-methoxycinnamaldehyde, and 5-formylfurfurol, were isolated from the stem bark of Duabanga grandiflora. The structures of these compounds were elucidated on the basis of spectroscopic analysis. Several of these metabolites were evaluated for cytotoxic activities against six cancer cell lines.

Hybrid flavan-chalcones, aromatase and lipoxygenase inhibitors, from Desmos cochinchinensis.

Hybrid flavan-chalcones, desmosflavans A (1) and B (2), together with three known compounds, cardamonin (3), pinocembrin (4) and chrysin (5), were isolated from leaves of Desmos cochinchinensis. Cardamonin (3) and chrysin (5) exhibited potent antioxidant activity with 15.0 and 12.2 ORAC units. Desmosflavans A (1) and B (2), pinocembrin (4), and chrysin (5) were found to be inhibitors of aromatase with respective IC50 values of 1.8, 3.3, 0.9, and 0.8 µM. Desmosflavan A (1) inhibited lipoxygenase with the IC50 value of 4.4 µM. Desmosflavan A (1) exhibited cytotoxic activity with IC50 values of 0.29-3.75 µg/mL, while desmosflavan B (2) showed IC50 values of 1.71-27.0 µg/mL.

Diketopiperazines and phthalides from a marine derived fungus of the order pleosporales.

Five metabolites, ( Z)-6-benzylidene-3-hydroxymethyl-1,4-dimethyl-3-methylsulfanylpiperazine-2,5-dione ( 1), (3S,3'R)-3-(3'-hydroxybutyl)-7-methoxyphthalide ( 2), ( S)-3-butyl-7-methoxyphthalide ( 3), (3R,6R)-bisdethiodi(methylthio)hyalodendrin ( 4), and bis- N-norgliovictin ( 5), were isolated from the culture broth of the marine derived fungus of the order Pleosporales strain CRIF2. Compounds 1 and 2 are new fungal metabolites, while 3 was isolated for the first time as a natural product. Compounds 1, 3, and 4 exhibited only weak cytotoxic activity, while 5 was inactive at 50 microg/mL.

Isoquinoline derivatives as potential acetylcholinesterase inhibitors.

Several bisbenzylisoquinoline alkaloid derivatives showed the inhibitory activity at acetylcholinesterase enzyme (AChE) in micromolar range. It is possible that monomeric moiety of bisbenzylisoquinoline alkaloid might be required for acetylcholinesterase enzyme inhibition. AChE inhibitory activity of related monomeric 1-benzylisoquinolines was examined by using Ellman colorimetric assay with galanthamine as a reference standard.