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The aim of the present study is to report the isolation, structural elucidation, and antiviral evaluation of four new withanolide-type steroids, named nicansteroidins A-D (1-4), together with nine related known compounds (5-13) isolated from the aerial parts of Physalis nicandroides. Their structures were established based on an extensive spectroscopic analysis, including 1D and 2D NMR techniques. Outstandingly, nicansteroidins A and B possess an unusual side chain with an exocyclic double bond on the δ-lactone system, whereas nicansteroidins C and D have an uncommon cycloperoxide functionality in ring A as distinct structural motifs. Their biological evaluation as inhibitors of human immunodeficiency virus type 1 replication revealed that two compounds from this series, 7 and 13, displayed strong inhibition of HIV-1 replication with IC50 values lower than 2 μM. Moreover, cellular mechanism experiments showed that the main target of these compounds in the HIV replication cycle is viral transcription. This study is the first report of withanolide-type steroids as HIV inhibitors and provides insight into their potential as candidates for further preclinical studies.

FXR is a member of the nuclear receptor superfamily and bile acids are endogenous ligands of FXR. FXR activation has recently been reported to inhibit intestinal inflammation and tumour development. This study aimed to investigate whether the novel FXR agonist nelumal A, the active compound of the plant Ligularia nelumbifolia, can prevent colitis and colorectal carcinogenesis. In a mouse colitis model, dextran sodium sulfate-induced colonic mucosal ulcer and the inflammation grade in the colon significantly reduced in mice fed diets containing nelumal A. In an azoxymethane/dextran sodium sulfate-induced mouse inflammation-related colorectal carcinogenesis model, the mice showed decreased incidence of colonic mucosal ulcers and adenocarcinomas in nelumal A-treated group. Administration of nelumal A also induced tight junctions, antioxidant enzymes, and FXR target gene expression in the intestine, while it decreased the gene expression of bile acid synthesis in the liver. These findings suggest that nelumal A effectively attenuates colonic inflammation and suppresses colitis-related carcinogenesis, presumably through reduction of bile acid synthesis and oxidative damage. This agent may be potentially useful for treatment of inflammatory bowel diseases as well as their related colorectal cancer chemoprevention.

Polysaccharides from plants and fungi are considered nowadays as powerful pharmacological tools with a great therapeutic potential. In the meantime, efforts have been addressed to set up effective chemical modifications of naturally occurring polysaccharides to improve their biological effects as well as to positively modify some key parameters like solubility, bioavailability, pharmacokinetic, and similar. To this concern much attention has been focused during the last decade to the selenylation of natural polysaccharides from plants, algae, and fungi, the use of which is already encoded in ethnomedical traditions. The aim of this review article is to provide a detailed survey of the in so far reported literature data and a deeper knowledge about the state of the art on the chemical and pharmacological properties of selenylated polysaccharides of plant, algal, and fungal origin in terms of anti-oxidant, anti-cancer, anti-diabetic, and immunomodulatory activities. In all cases, literature data revealed that selenylation greatly improved such properties respect to the parent polysaccharides, indicating that selenylation is a valid, alternative, and effective chemical modification of naturally occurring carbohydrates.

An efficient analytical strategy based on different extraction methods of biologically active naturally occurring oxyprenylated umbelliferone and ferulic acid derivatives 7-isopentenyloxycoumarin, auraptene, umbelliprenin, boropinic acid, and 4'-geranyloxyferulic acid and quantification by UHPLC with spectrophotometric (UV/Vis) detection from Tea tree oil is reported. Absorption of the pure oil on Al2O3 (Brockmann activity II) prior washing the resulting solid with MeOH and treatment of this latter with CH2Cl2 resulted the best extraction methodology in terms of yields of oxyprenylated secondary metabolites. Among the five O-prenylphenylpropanoids herein under investigation auraptene and umbelliprenin were never detected while 4'-geranyloxyferulic acid was the most abundant compound resulting from all the three extraction methods employed. The UHPLC analytical methodology set up in the present study resulted to be an effective and versatile technique for the simultaneous characterization and quantification of prenyloxyphenylpropanoids in Tea tree oil and applicable to other complex matrices from the plant kingdom.

In this paper the presence of selected prenylated and unprenylated phenylpropanoids of nutraceutical value, namely umbelliferone, apigenin, 4'-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene, and umbelliprenin have been determined in all parts of the edible herb Amaranthus retroflexus extracted with different methodologies. Roots were seen to contain the widest variety of unprenylated and prenylated phenylpropanoids both in terms of number of secondary metabolites and their quantitites. Findings described in the present study underline how A. retroflexus can be considered as a potential nutraceutical for human welfare.

Background Glucose transporter 4 (GLUT4) is firmly established to play a pivotal role in glucose metabolism and in particular in modulating the insulin-stimulated glucose transport in several tissues, such as skeletal muscle and adipose tissue. Stimulation of GLUT4 by insulin results in its translocation to the plasma membrane, activation of several kinases, and finally in a large glucose influx into cells. Purpose In this study we investigated the modulating properties of four biologically active oxyprenylated ferulic acid and umbelliferone derivatives and of their unprenylated parent compounds on GLUT-4 mediated glucose uptake and translocation. Methods Oxyprenylated phenylpropanoids have been synthesized in high yields and purity by already reported methodologies. All the synthesized chemicals were tested for their capacity to modulate GLUT4 mediated glucose uptake and GLUT4 translocation in L6 rat skeletal myoblasts in the concentration range 0.1 – 10 µM. Insulin (0.1 µM) was used as positive control. Western blot analysis was employed to assess if GLUT4 translocation occurred prior to increase of glucose uptake. Statistical analyses were carried out by the Dunnett multiple comparison test. Results 4′-Geranyloxyferulic acid (GOFA), 7-isopentenyloxycoumarin, and auraptene (7-geranyloxycoumarin) increased glucose uptake in a concentration-dependent manner, and significant increases were observed at 0.1 µM for GOFA, and 10 µM for 7-isopentenyloxycoumarin, and auraptene. These products also were able to significantly promote the translocation of GLUT4 to the plasma membrane of L6 myotubes. After treatment with compounds for 15 min, the incorporated amounts of GOFA, 7-isopentenyloxucoumarin, and auraptene were 0.15, 0.32, and 1.77 nmols/60-mm culture dish, respectively. A sample of raw Italian propolis, found to be rich in GOFA and auraptene, was also seen to mimic insulin-effect in the concentration range 0.01 – 1.0 mg/ml. Conclusions Among the compounds assayed, auraptene showed to possess potentialities to be a potent activator of both translocation of GLUT4 and glucose influx into skeletal muscle cells with the highest bioavailability among effective compounds. Its capacity to modulate sugar metabolism, coupled to its presence in edible Citrus fruits, can be regarded as an additional reason to account for the already known stimulating properties of some vegetable (e.g. bitter orange).

A series of naturally occurring 3,3-dimethylallyloxy- and geranyloxycoumarins and alkaloids were chemically synthesized and tested as anti-inflammatory agents for their inhibitory effects on nitric oxide production in LPS-stimulated RAW 264.7 cells. Results indicated that the alkaloid of fungal origin 3-methylbut-2-enyl-4-methoxy-8-[(3-methylbut-2-enyl)oxy]quinoline-2-carboxylate, commonly known as Ppc-1, and coumarins having an unsubstituted 2-benzopyrone ring exhibited the highest activity with IC 50 values from 23 to 34 μM without having poor or not detectable cytotoxicity. Indomethacine and L-NAME used as reference drugs provided by far less activities.

Background: Quinonemethide triterpenoids, known as celastroloids, constitute a relatively small group of biologically active compounds restricted to the Celastraceae family and, therefore, they are chemotaxonomic markers for this family. Among this particular type of metabolite, pristimerin and tingenone are considered traditional medicines in Latin America. The aim of this study was the isolation of the most abundant celastroloids from the root bark of Maytenus chiapensis, and thereafter, to develop an analytical method to identify pristimerin and tingenone in the Celastraceae species. Methods: Pristimerin and tingenone were isolated from the n-hexane-Et2O extract of the root bark of M. chiapensis through chromatographic techniques, and were used as internal standards. Application of a validated RP HPLC-PDA method was developed for the simultaneous quantification of these two metabolites in three different extracts, n-hexane-Et2O, methanol, and water, to determine the best extractor solvent. Results: Concentration values showed great variation between the solvents used for extraction, with the n-hexane–Et2O extract being the richest in pristimerin and tingenone. Conclusions: M. chiapensis is a source of two biologically active quinonemethide triterpenoids. An analytical method was developed for the qualification and quantification of these two celastroloids in the root bark extracts of M. chiapensis. The validated method reported herein could be extended and be useful in analyzing Celastraceae species and real commercial samples.

The chromane core is widely represented in nature being part of a wide array of secondary metabolites of plant, fungal, and bacterial origin. In this paper an improved method for the chemical synthesis of differently substituted chromanes is described. Substituted 2H-1-benzopyrans have been synthesized in good to excellent yields (52–81%) by treatment of 3,3-dimethylallyl and propenylbenzene ethers of differently substituted phenols with phenylselenyl chloride.

A series of naturally occurring and semisynthetic O-geranyl cinnamic acids and their conjugates with the iNOS inhibitor Nω-nitro-L-arginine methyl ester have been synthesized and evaluated for their effects on expressions of COX-2 and iNOS, antioxidant activity, and PGE2 and NO production in LPS-stimulated U937 mononuclear cells. All adducts showed little or no effect on iNOS functionality in terms of NO release. A much more significant activity has been recorded on PGE2 biosynthesis for which the sample substituted with a -NO2 group in position 3 of the aromatic ring revealed an effect in the nM range both for the L-NAME conjugated product and the parent compound (IC50=0.71 μM and 0.1 μM respectively). Preliminary docking studies have been carried out to clarify the mechanism of COX-2 inhibition, and they suggest that the geranyloxy side chain is likely to play an important role for the observed activity and that structural modifications are able to tune such effects.

Crop-derived products, like juices obtained from edible fruits and vegetables, and waste waters deriving from agricultural and industrial processing have been recently exploited to efficiently promote several ‘classic’ and innovative synthetic organic reactions. Such a green chemical approach prevented the use of toxic, polluting, and hazardous materials and in the mean time allowed to increase the commercial values of crop products and industrial byproducts. Coumarin-3-carboxylic and cinnamic acids represent classes of naturally occurring and semi-synthetic compounds with interesting and promising pharmacological activities. In this Letter a new and improved methodology for the Knoevenagel condensation yielding the title compounds using juices from edible fruits and vegetables (lemon, grapefruit, carrot, pomegranate, kiwi, vinegar, tomato), liqueurs (limoncello), and waste waters (buttermilk and residues of olive processing) as solvents is described. Coumarin-3-carboxylic and cinnamic acids have been synthesized in excellent yields by ultrasound irradiation from differently substituted 2-hydroxybenzaldehydes, 2-hydroxyacetophenones, and benzaldehydes, and Meldrum’s acid as starting substrates. The findings described herein enforce the concept of the usefulness of products and byproducts derived from agriculture and food industry to accomplish green chemical processes.

Coumarins are a well-known class of natural occurring and semi-synthetic products with reported important and effective pharmacological activities. In this Letter an improved method for the chemical synthesis of such compounds is described. Coumarins have been obtained in good to excellent yields under microwave irradiation and solvent-free conditions in a short time from differently substituted phenols and propiolic acids used as starting materials in the presence of Yb(OTf) 3 hydrate 10% mol as the catalyst.

2-Amino-4H-pyrane derivatives are nowadays well recognized as valuable scaffold in drug discovery. In this manuscript a new and improved multicomponent process for the chemical synthesis of the title compounds is described. β-Dicarbonyl and activated cyanomethylene compounds, and aromatic, aliphatic or α,β-unsaturated aldehydes have been subjected to a three-component reaction under the catalysis of ytterbium triflate hydrate under solvent-free conditions at 50 °C, and by application of microwaves and ultrasounds. Of the three methodologies employed, the reaction in neat performed in a flask with magnetic stirring proved to be by far the most efficient, providing the desired adducts in very good yields (85–91%). The experimental protocol set-up in this study was applied without significant differences in terms of yields to aromatic aldehydes having electron withdrawing or electron-donating substituents, as well as to aliphatic and α,β-unsaturated ones. Moreover ytterbium triflate has been easily recovered from each reaction media and reused without appreciable loss of its catalytic activity.

A simple and easy to handle extraction procedure based on the use of electromagnetic induction heating is described. To assess the potential, scopes, and limitations of this novel process, extraction and subsequent HPLC quantification of emodin from an hydroalcoholic extract of rhizome of Rheum palmatum (Chinese rhubarb) was selected as the reference experiment. Maceration at room temperature and by heating, ultrasound-assisted, and microwave-assisted extractions were also carried out for comparison. Results obtained with electromagnetic induction heating showed that this methodology performed largely better both in terms of time process and extraction yields.

Spinach leaves, goji berries and quinoa seeds are claimed to have a great nutraceutical potential due to their high content of compounds providing benefits for human health, such as amino acids, polyunsaturated fatty acids, carotenoids, betaine, vitamins, fibre, minerals and polyphenols. Samples of these plants were extracted with different solvent mixtures (e.g. EtOH, H2O/EtOH 3:7 and H2O/EtOH 7:3) and extractions were accomplished using a microwave apparatus. Subsequent UHPLC analysis and photodiode array detection were employed for the quantification of biologically active compounds like 7-isopentenyloxycoumarin, auraptene, umbelliprenin, boropinic acid and 4′-geranyloxyferulic acid. EtOH was found to be the best solvent in terms of extractive yields and the above-mentioned phytochemicals were recorded in the concentration range 2.01–49.22 µg/g dry extract. The findings depicted herein revealed that spinach, goji and quinoa are good sources of oxyprenylated umbelliferone and ferulic acid derivatives.

Naturally occurring coumarins 7-isopentenyloxycoumarin, auraptene, and umbelliprenin are able to modulate the biosynthesis of melanin in murine Melan-a cells probably through the interaction with selected biological targets like estrogen receptor β and aryl hydrocarbon receptor. Such a modulation strictly depends on the individual structure of the coumarin: the presence of a 3,3-dimethylallyloxy side chain is a structural determinant for tanning activation whereas a farnesyl one leads to the opposite effect. The parent compound with a free OH group, umbelliferone, did not provide any interaction. Other coumarins assayed, having shorter chains and/or being substituted in other positions, and prenyloxypsoralens, were not active or not further investigated in this context being cytotoxic at low doses.

A series of seven oxyprenylated phenylpropanoids and naphthoquinones were tested regarding their ability to activate transient receptor potential ankyrin subtype 1 channel (TRPA1). Three of the assayed compounds, namely, boropinal (3), juglone (5), and plumbagin (7), acted as strong modulators of TRPA1 channels with EC50 values of 9.8, 1.7, and 0.5 mu M, respectively, as assessed by Ca2+ assays. Moreover, the compounds elicited TRPA1 currents in electrophysio-logical whole cell recordings. We additionally provide evidence that plumbagin activated TRPA1-positive neurons isolated from mouse dorsal root ganglion neurons but did not affect sensory neurons from TRPAl-deficient mice. The high potencies of plumbagin and juglone to activate TRPA1 channels may explain the molecular basis of the mucosal irritant properties of these compounds as well as of related naphthoquinones and phytopreparations, as widely reported in the literature.

Natural honey has been employed as a nutraceutical agent with benefits and therapeutic promises for humans for many centuries. It has been largely used as food and medicine by all generations, traditions, and civilizations, both ancient and modern. Several chemicals having beneficial effects for human health have been reported as components of natural honey and these include sugars, organic acids, aminoacids, minerals, and vitamins. Also some important phytochemicals have been described and these comprise tannins, flavonoids, terpenes, saponins, and alkaloids. In this note it is described the successful application of a RP HPLC-UV-vis method for the separation and quantification of 4'-geranyloxyferulic acid (GOFA) in four honey samples of different origin. Concentration values showed a great variation between the four samples tested, being chestnut honey the one richest in GOFA (7.87 mg/g). The findings described herein represent the first example reported in the literature of the characterization of an oxyprenylated phenylpropanoid in honey.

Coumarins are a group of heterocyclic compounds naturally present in a large variety of plant families. Nevertheless, oxyprenylated coumarins have been only recently seen as valuable and promising biologically active phytochemicals. In this study, we synthesized three naturally occurring O- prenylcoumarins ( 1 ), ( 2 ), and ( 3 ), and evaluated their antibacterial and anti-inflammatory properties in view of their therapeutic potential against periodontal disease. The three O- prenylcoumarins were synthesized using well-known schemes leading to the chromen-2-one nucleus. The periodontal pathogen Porphyromonas gingivalis was found to be highly susceptible to all three O- prenylcoumarins with minimal inhibitory concentration values in the range of 12.5–25 mg/ml; the non-prenylated forms of the coumarins did not show any activity. The antibacterial activity of ( 1 ), ( 2 ), and ( 3 ) appeared to result from its ability to permeate the cell membrane. Using the U937-3xkB-LUC human monocytic cell line, compounds ( 2 ) and ( 3 ) dose-dependently inhibited lipopolysaccharide-induced NF-kB activation, while ( 1 ) did not. The non-prenylated forms of the coumarins were either inactive or much less potent. In conclusion, O- prenylcoumarins ( 2 ) and ( 3 ) by exhibiting a dual mode of action including antibacterial and anti-inflammatory activities may represent promising targeted therapeutic agents for localized treatment of periodontal diseases.

Fiorito S., Epifano F., Taddeo V.A., Genovese S. (2015): Oxyprenylated ferulic acid derivatives in Italian citrus liqueurs. Czech J. Food Sci., 33: 237–241. 4'-Geranyloxyferulic and boropinic acid have been recently found as phytochemicals exerting promising pharmaco logical effects as cancer chemopreventive, anti-inflammatory, neuroprotective, and antiHelicobacter pylori agents. An RP HPLC-UV/Vis method for the qualitative and quantitative analysis of these oxyprenylated derivatives in hand made citrus-based typical Italian liqueurs like limoncello, arancello, and mandarinetto was successfully performed. Concentration values showed a great variation between the different liquors, limoncello, from Abruzzo region, being the richest one both in 4’-geranyloxyferulic acid (1.68 ± 0.03 µg/ml of liquor) and boropinic acid (0.16 ± 0.01 µg/ml). Only in two cases boropinic acid was not detected.

In this paper we established the effect on the extent of the geranylation step of selected O-prenyl phenylpropanoids by their biosynthetic precursors (e.g. ferulic acid and umbelliferone) in cultured calli from Anethum graveolens L. Lyophilized vegetable material has been extracted by an overnight maceration with EtOH and 3,3-dimethylallyl, geranyl, and farnesyl derivatives of both ferulic acid and umbelliferone quantified by HPLC analysis coupled to UV/Vis detection. In no case culture media supplemented with the parent molecule provided increases in the biosynthesis of the corresponding prenylated secondary metabolite. Quite surprisingly ferulic acid and umbelliferone exerted opposite effects, the first being an elicitor of the only O-geranylation of phenylpropanoid cores while the latter was seen to largely suppress this biosynthetic step.

Cultured calli from Anethum graveolens L. have been previously shown to biosynthetically manipulate selected precursors having a phenylpropanoid core leading to an increase or a decrease in their prenylation. In this article, an extension of previous studies in this field showing how two other cinnamic acid derivatives, namely p-coumaric acid and boropinic acid, are able to exert similar effects using the same experimental model will be reported. Lyophilized calli from A. graveolens has been powdered and extracted by an overnight maceration with EtOH. Selected oxyprenylated cinnamic acid derivatives were then quantified by HPLC analysis coupled to UV/Vis detection. The effect recorded after administration of p-coumaric acid was similar to that evoked by ferulic acid and consisted in a selective increase of its geranylation. The addition of boropinic acid stimulated the biosynthesis of ferulic acid with longer chain like 4′-farnesyloxyferulic acid. This study demonstrated that administration to cultured calli of phenylpropanoids with no free OH moiety has a deep influence on the prenylation biosynthetic pathways and led to the hypothesis that the elongation of the O-side chain of oxyprenylated cinnamic acid derivatives may occur by addition in sequence of isoprenic units.

Xanthones represent a class of naturally occurring compounds with valuable and promising reported pharmacological activities. One of the main disadvantages in the use of such products is related to the difficulties in their chemical synthesis. In this Letter a new and improved method for the chemical synthesis of xanthones is described. The title compounds have been synthesized in good yields under microwave irradiation from substituted 2-hydroxybenzoic acids and phenols in the presence of Yb(OTf)3 hydrate as the catalyst.

Umbelliprenin is a secondary plant metabolite that displays promising chemopreventive, anti-inflammatory, and antigenotoxic properties. It possesses potential for applications to human welfare notably to prevent the emergence of cancer. For this purpose, stability studies are needed to define proper storage conditions and adapted formulations for this drug candidate. The identification of degradative products is a major concern for the preclinical development of umbelliprenin, providing also interesting information related to potential original phytochemicals formed in plants exposed to stressors. The stability profile of umbelliprenin under various stress conditions including exposure to heat, light, oxidation, and hydrolytic medium was assessed via HPLC/UV data. The data support that umbelliprenin undergoes inter- and intramolecular [2+2] cycloaddition under light exposure, leading respectively to a cyclobutane-umbelliprenin dimer and a 16-membered macrocycle. Their structures were characterized via MS and NMR data. It was shown that UV-A filters prevent this process, whereas UV-B filters and antioxidants are not or weakly effective. The study provides useful information for the preclinical development of umbelliprenin as an original chemopreventive agent.

Human organic anion transporters hOAT1/SLC22A6 and hOAT3/SLC22A8 are highly expressed on the basolateral membrane of renal proximal tubules and mediate tubular uptake of anionic drugs from blood. They play an important role for drug disposition, and therefore close studies of their ligand recognition are important for drug therapy and development. In this study, we performed uptake experiments using HEK293 and fluorescent anion 6-carboxyfluorescein to asses the effects of phenylpropanoids on hOAT1 and hOAT3. We found that phenylpropanoids, 3-(4'-isopentenyloxyphenyl)-benzoic acid (IBA), 3-(4'-isopentenyloxy-3'-methoxyphenyl)-benzoic acid (IMBA), and 3-(4'-geranyloxy-3'-methoxy phenyl)-benzoic acid (GMBA) inhibited hOAT1 and hOAT3. The Ki values for hOAT1 were comparable to that of probenecid, a strong inhibitor of hOAT1 and hOAT3. While IBA demonstrated competitive inhibition, IMBA and GMBA showed mixed-type inhibition. After preincubation and washout, the inhibitory effects remained with IMBA and GMBA but not IBA, suggesting that the functional group at 3'-position is responsible for these differences. In conclusion, IBA, IMBA, and GMBA are inhibitors of hOAT1 and hOAT3.

Oxyprenylated secondary metabolites from plants, fungi, and bacteria, and their semisynthetic derivatives have been subject of growing interest during the last decade. Such natural products in fact have been discovered as potentially novel lead compounds for a series of pharmacological activities, mainly in terms of anti-cancer and anti-inflammatory ones. Especially during the last 5 years, a wider panel of prenyloxy secondary metabolites have been investigated from chemical and biological points of view and these include benzoic acids, alcohols, aldehydes, chalcones, anthraquinones, 1,4-naphthoquinones, other than the well known oxyprenylated ferulic acid and coumarin derivatives. The aim of this comprehensive review is to focus on the anti-inflammatory properties and related mechanisms of action of selected classes of oxyprenylated naturally occurring compounds and their semisynthetic analogues covering the literature period from 2011 to 2017. In vitro and in vivo data on their pharmacological activity triggering different pathways of the overall inflammatory machinery as well as structure activity relationship acquisitions will be summarized in order to make a detailed survey of the most recent reports on the potential of the title compounds as a novel class of anti-inflammatory agents.

A green dispersive liquid-liquid microextraction (DLLME) using deep eutectic solvent (DES) as the extracting solvent has been developed and applied for the simultaneous quantification of ferulic acid, umbelliferone, boropinic acid, 7-isopentenyloxycoumarin, 4'-geranyloxyferulic acid (GOFA), and auraptene in some vegetable oils using ultra high performance liquid chromatography (UHPLC) with photodiode array detection (PDA). All parameters in the extraction step, including selection and loading of both extracting and dispersing solvents, amount of both extractant and disperser solvent were investigated and optimized. PhAA/TMG DES achieved higher recovery and enrichment factor compared to other DESs. The validated method showed good linearity with correlation coefficients, r2>0.9990 for all the analytes. Furthermore, this is the first time that eco-friendly solvents are used for the extraction of oxyprenylated phenylpropanoids and the corresponding extract analyzed with ultra high performance liquid chromatography with photodiode array detection.

3-(4′-Geranyloxy-3′-methoxyphenyl)-2-trans propenoic acid (4′-geranyloxyferulic acid, GOFA) 1 is an oxyprenylated ferulic acid derivative that has been extracted for the first time in 1966 from the root and bark extracts of Acronychia baueri Schott (Fam. Rutaceae). In the last decade the pharmacological properties of the title compound began to be characterized, revealing its valuable potentialities as an anti-inflammatory and anti-tumor agent. In this context the aim of this review article is to report the insofar described biological effects of 4′-geranyloxyferulic acid. Data collected during the recent years indicates that 1 is an effective dietary feeding colon cancer chemopreventive agent in vivo. When administered to animals, in which colon adenoma and adenocarcinoma have been induced by the administration of azoxymethane in the diet, as a large bowel delivered prodrug linked to dipeptides, or as an inclusion complex in cyclodextrins, or coupled to known anti-inflammatory agents like L-NAME, a protective effect on colon cancer growth and development have been recorded. Recent studies on the natural occurrence of 4′-geranyloxyferulic acid, showed the presence of this oxyprenylated secondary metabolite in widely consumed edible fruits and vegetables like citrus fruits and their phytopreparations.

Chenopodium quinoa Wild is a &ldquo, pseudocereal&rdquo, grain which attracts a lot of attention in the scientific community as it has a positive effect on health. Here, we investigate the presence of biologically active O-prenylated phenylpropanoids in the ethanol extract of commercially available quinoa seeds. We claim that 4&prime, Geranyloxyferulic acid (GOFA) was the only phytochemical product found that belongs to quinoa&rsquo, s group secondary metabolites. We studied the changes in the oxidative and inflammatory status of the cellular environment in HCT 116 cell line processed with quinoa extract and its component GOFA, the implementation was done through the analysis of the antioxidant enzymes (SOD and CAT), the pro-inflammatory components (iNOS, IL-6 and TNF-&alpha, ), and the products of intermediary metabolism (ONOO&minus, O2&minus, ). Moreover, the l-arginine uptake was proposed as a target of the tested compounds. We demonstrated that the GOFA, through a decrease of the CAT-2B expression, leads to a reduction of the l-arginine uptake, downregulating the harmful iNOS and restoring the altered redox state. These results propose a new molecular target involved in the reduction of the critical inflammatory process responsible for the cancer progression.

Coumarin-3-carboxylic acids represent a class of natural occurring and semi-synthetic products with valuable reported pharmacological activities. In this Letter a new and improved method for the chemical synthesis of the title compounds is described. Coumarin-3-carboxylic acids have been synthesized in good to excellent yields under microwave irradiation and solvent-free conditions from differently substituted 2-hydroxybenzaldehydes or 2 hydroxyacetophenones and Meldrum’s acid as starting materials in the presence of Yb(OTf)3 hydrate 5% mol as the catalyst.

The aryl hydrocarbon receptor (AhR) is a transcription factor activated by a vast array of natural and synthetic ligands. It plays a pivotal role in numerous physiological and pathological responses, such as cell proliferation and differentiation, induction of xenobiotic metabolizing enzymes, response to environmental toxins, and several others. In this study, we investigated the ability of some natural compounds (oxyprenylated ferulic acid and umbelliferone derivatives) and their semisynthetic analogues (e.g., differently substituted 7-alkoxycoumarins) to activate AhR, using a reporter luciferase assay. Among them, we found that 7-isopentenyloxycoumarin was the best AhR activator. Boropinic acid, 7-but-2'-enyloxycoumarin, 7-(2',2'-dimethyl-n-propyloxy)coumarin, 7-benzyloxycoumarin, and 7-(3'-hydroxymethyl-3'-methylallyloxy)coumarin were also active, although to a lesser extent. All the compounds were also analyzed for their ability to inhibit AhR activation, using a reference ligand, 6-formylindolo[3,2-b]carbazole. Data recorded in the present investigation pointed out the importance of a 3,3-dimethylallyloxy side chain attached to the coumarin ring core as a key moiety for AhR activation.

In patients with Parkinson’s disease (PD), hyperactivated inflammation in the brain, particularly microglial hyperactivation in the substantia nigra (SN), is reported to be one of the triggers for the delayed loss of dopaminergic neurons and sequential motor functional impairments. We previously reported that (1) auraptene (AUR), a natural prenyloxycoumain, suppressed inflammatory responses including the hyperactivation of microglia in the ischemic brain and inflamed brain, thereby inhibiting neuronal cell death; (2) 7-isopentenyloxycoumarin (7-IP), another natural prenyloxycoumain, exerted anti-inflammatory and neuroprotective effects against excitotoxicity; and (3) 4′-geranyloxyferulic acid (GOFA), a natural prenyloxycinnamic acid, also exerted anti-inflammatory effects. In the present study, using an intranigral lipopolysaccharide (LPS)-induced PD-like mouse model, we investigated whether AUR, 7-IP, and GOFA suppress microglial activation and protect against dopaminergic neuronal cell death in the SN. We successfully showed that these prenyloxyphenylpropanoids exhibited these prospective abilities, suggesting the potential of these compounds as neuroprotective agents for patients with PD.

Coumarins are a well-known class of natural occurring and semi-synthetic products with reported important and effective pharmacological activities. In this Letter an improved method for the chemical synthesis of such compounds is described. Coumarins have been obtained in good to excellent yields under microwave irradiation and solvent-free conditions in a short time from differently substituted phenols and propiolic acids used as starting materials in the presence of Yb(OTf) 3 hydrate 10% mol as the catalyst.

An analytical strategy based on different extraction methodologies and HPLC with spectrophotometric (UV-vis) detection has been developed to investigate the presence of and to quantitate biologically active selected unprenylated and O-prenylated phenylpropanoids, namely umbelliferone, 4'-geranyloxyferulic acid, 7-isopentenyloxycoumarin, auraptene, and umbelliprenin in dill (Anethum graveolens L.), anise (Pimpinella anisum L.), and wild celery (Angelica archangelica L.). Absolute ethanol or 7:3 water/ethanol mixtures were seen to be the most powerful extraction solvents to perform "classic" maceration or ultrasound-assisted one in terms of yields in secondary metabolites. For anethum and anise, umbelliprenine was found to be the most abundant prenyloxy secondary metabolite, while in wild celery 4'-geranyloxyferulic acid recorded the highest concentration. Our experimental approach demonstrated to be efficient for the simultaneous identification and quantitation of the above mentioned prenyloxyphenylpropanoids in the title plant species, that is reported herein for the first time in the literature.

Oxyprenylated natural products were shown to exert in vitro and in vivo remarkable anti-cancer and anti-inflammatory effects. This paper describes a rapid, selective, and sensitive HPLC method with fluorescence detection for determination of 4'-geranyloxyferulic acid (GOFA) and its conjugate with l -nitroarginine methyl ester (GOFA-L-NAME) in mononuclear cells. Analytes were extracted from cells using methanol and eluted on a GraceSmart RP 18 analytical column (250 × 4.6 mm i.d., 5 μm particle size) kept at 25 °C. A mixture of formic acid 1% in water (A) and methanol (B) were used as mobile phase, at a flow-rate of 1.2 mL/min in gradient elution. A fluorescence detector (excitation/emission wavelength of 319/398 nm for GOFA and GOFA-L-NAME), was used for the two analytes. Calibration curves of GOFA and GOFA-L-NAME were linear over the concentration range of 1.0–50 μg/mL, with correlation coefficients ( r 2 ) ≥ 0.9995. Intra- and inter-assay precision do not exceed 6.8%. The accuracy was from 94% to 105% for quality control samples (2.0, 25.0 and 40 μg/mL). The mean (RSD%) extraction recoveries (n = 5) for GOFA and GOFA-L-NAME from spiked cells at 2.0, 25.0 and 40.0 μg/mL were 92.4 ± 1.5%, 94.7 ± 0.9% and 93.8 ± 1.1%, for GOFA and 95.3 ± 1.2%, 94.8 ± 1.0% and 93.9 ± 1.3%, for GOFA-L-NAME. The limits of detection and quantification were 0.3 μg/mL and 1.0 μg/mL for GOFA and GOFA-L-NAME. This method was successfully applied to measure GOFA and GOFA-L-NAME concentrations in a mononuclear cells.

In this paper the presence of selected prenylated and unprenylated phenylpropanoids, namely ferulic acid 1, boropinic acid 2, 4'-geranyloxyferulic acid 3, umbelliferone 4, 7-isopentenyloxycoumarin 5, and auraptene 6, have been determined in Italian raw propolis after having been extracted with different methodologies. An aqueous solution of β-cyclodextrin was the best extraction method for ferulic acid 1, treatment with indifferently EtOH or aqueous β-cyclodextrin were the most effective one for umbelliferone 4, boropinic acid 2 gave the best yields either with H2O/β-cyclodextrin or olive oil treatment or in biphasic systems, maceration with biphasic mixtures of aqueous β-cyclodextrin and olive oil was seen to be the most effective procedure for 7-isopentenyloxycoumarin 5, the only method providing significant quantities of 4'-geranyloxyferulic acid 3 was the maceration of raw propolis with olive oil, and finally auraptene 4 was best extracted with absolute EtOH. "Classic" maceration in general performed better than ultrasound-assisted one.

Umbelliprenin has recently been shown to have great potential as a skin whitening agent. Wishing to investigate the same effect in plant species known to biosynthesize this coumarin, three plants belonging to the Apiaceae family, namely Anethum graveolens L. (dill), Pimpinella anisum L. (anise), and Ferulago campestris (Besser) Grecescu (field ferula) were screened by HPLC analysis for their respective content of umbelliprenin in extracts obtained with different solvent mixtures and by maceration and ultrasound-assisted processes. EtOH was shown to be the best solvent, providing umbelliprenin yields ranging from 1.7% to 14.4% (with respect to the total amount of extract obtained). Extracts with the highest content of this farnesyloxycoumarin were then assayed as modulators of melanogenesis in cultured murine Melan A cells employing the same umbelliprenin obtained by chemical synthesis as the reference. A parallelism between the content of the coumarin and the recorded depigmenting effect (60% for the EtOH extract of F. campestris as the best value) was revealed for all plants extracts when applied at a dose of 100 μg/mL. Our results demonstrate that the same potential of umbelliprenin can be ascribed also to umbelliprenin-enriched plant extracts which reinforces enforce the widespread use of phyto-preparations for cosmetic purposes (e.g., A. graveolens).

The phytochemical composition of Lactuca sativa L. var. crispa, commonly known as crisphead lettuce, from Morocco has been re-investigated for the presence of oxyprenylated cinnamic acid and coumarin derivatives. In the mean time also the anti-oxidant and anti-inflammatory effects of extracts from leaves obtained by the use of a Soxhlet apparatus have been assessed. The extracts had a high content of polyphenols with remarkable differences ranging from 0.19 to 0.38 mg gallic acid eq/mg, while the content of flavonoids ranged from 3.75 to 9.64 mg catechin eq/g. The hydroalcoholic extract with a polarity index of 5.8 displayed the best anti-oxidant, radical scavenging, and anti-inflammatory activities. The same extracts were screened by reverse-phase HPLC-UV/V analysis for the presence of biologically active oxyprenylated phenylpropanoids. Only 4'-geranyloxyferulic acid was recorded in detectable amounts. Results described herein enforce the nutraceutical value and depict a potential chemopreventive dietary feeding role for crisphead lettuce.

An efficient synthesis of differently substituted furans from acetylene dicarboxylates and β-dicarbonyl compounds is described. The furan nucleus was built by means of an Yb(OTf)3 catalyzed cycloaddition reaction yielding desired adducts in 91% – 98% yield.

Elastic and ultradeformable liposomes were synthesized and physicochemically characterized to make suitable topical formulations for delivering the anti-inflammatory and anticancer compound 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid. The average sizes of elastic and ultradeformable liposomes are below 300 nm, while the size distribution and Z-potential are below 0.3 and − 25 mV, respectively. The presence of 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid does not affect the physicochemical parameters of nanovesicles. Elastic and ultradeformable liposomes show a zero order release kinetic and are stable at room temperature for a long time with or without 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid. The ultradeformable liposomes are more deformable than elastic liposomes. These differences may depend on sodium cholate derivatives making nanoformulations. The 3-(4′-geranyloxy-3′-methoxyphenyl)-2-trans-propenoic acid-loaded elastic and ultradeformable liposomes can provide innovative nanotherapeutics-based natural compounds for the potential treatment of cutanous inflammation.

Juglone 1 an plumbagin 2 are plant secondary metabolites nowadays well known for their anticancer properties. In this study we synthesized analogues of 1 and 2 deriving from the functionalization of the OH group in position 5 with different side chains in form of esters and ethers. Therefore the growth inhibitory activities of these adducts were evaluated in vitro on six cancer cell lines using the MTT colorimetric assays along with the two natural parent compounds. The data revealed that these latter displayed the strongest growth inhibitory activities in vitro. Quantitative videomicroscopy analyses were then carried out on human U373 glioblastoma cells, which are characterized by various level of resistance to pro-apoptotic stimuli. We compared the naturally occurring reference compounds 1 and 2 with the derivatives exerting the best activities in terms of IC50 growth inhibitory values. These analyses showed that both juglone and plumbagin had a cytostatic effect on U373 cells and were able to overcome the intrinsic resistance of U373 cancer cells to pro-apoptotic stimuli.

A simple solvent-free protocol for the condensation reaction of 2-hydroxybenzaldehydes or 2-hydroxyacetophenones with Meldrum′s acid to afford the title products in good to excellent yields is developed.

Xanthones represent a class of naturally occurring compounds with valuable and promising reported pharmacological activities. One of the main disadvantages in the use of such products is related to the difficulties in their chemical synthesis. In this Letter a new and improved method for the chemical synthesis of xanthones is described. The title compounds have been synthesized in good yields under microwave irradiation from substituted 2-hydroxybenzoic acids and phenols in the presence of Yb(OTf)3 hydrate as the catalyst.