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The antiangiogenic activity of the ethanol extract of propolis collected from different regions in western Algeria was investigated using in vitro human umbilical vein endothelial cells (HUVECs). The ethanol extract with the strongest activity, i.e., Algerian propolis 1 (EEPA1), inhibited the formation of capillary networks in a dose-dependent manner (6.25–50 μg/mL) within 12 h and induced cell fragmentation of HUVECs at 50 μg/mL after treatment for 24 h. To identify the active compounds in EEAP1, a high-performance liquid chromatography (HPLC) analysis was performed, revealing that EEAP1 contains two major compounds. Both compounds were isolated by repeated column chromatography and identified as ω-hydroxyferulenol (1) and ferulenol (2), which have a coumarin structure conjugated with a farnesyl group according to NMR, high-resolution electrospray ionization mass spectroscopy, and chemical modification. Compounds 1 and 2 inhibited the tube-forming activity of HUVECs, especially 2, which exhibited a stronger antiangiogenic effect even at a low concentration of 3.31 μg/mL. Moreover, 2 suppressed the elongation and induced cell fragmentation at the same dose. The molecular changes in tube-forming HUVECs induced by 2 were found to be related to the activation of the caspase signals. To confirm the plant origin of propolis, an HPLC comparative analysis of the ethanol extracts of some plants near beekeeping areas and that of Algerian propolis (EEAP1) was performed, and similar chromatographic patterns were observed. This result suggests that the plant origin of this Algerian propolis is the resin of Ferula communis.

In recent decades, interest in natural compounds has increased exponentially due to their numerous beneficial properties in the treatment of various acute and chronic diseases. A group of plant derivatives with great scientific interest is terpenic compounds. Among the plants richest in terpenes, the genus Ferula L. is one of the most representative, and ferutinin, the most common sesquiterpene, is extracted from the leaves, rhizome, and roots of this plant. As reported in the scientific literature, ferutinin possesses antioxidant and anti-inflammatory properties, as well as valuable estrogenic properties. Neurodegenerative and demyelinating diseases are devastating conditions for which a definite cure has not yet been established. The mechanisms involved in these diseases are still poorly understood, and oxidative stress is considered to be both a key modulator and a common denominator. In the proposed experimental system, co-cultured human neurons (SH-SY5Y) and human oligodendrocytes (MO3.13) were treated with the pro-inflammatory agent lipopolysaccharide at a concentration of 1 μg/mL for 24 h or pretreated with ferutinin (33 nM) for 24 h and subsequently exposed to lipopolysaccharide 1 μg/mL for 24 h. Further studies would, however, be needed to establish whether this natural compound can be used as a support strategy in pathologies characterized by progressive inflammation and oxidative stress phenomena.

The employment studies of natural extracts in the prevention and treatment of several diseases highlighted the role of different species of genus Ferula L., belonging to the Apiaceae family, dicotyledonous plants present in many temperate zones of our planet. Ferula communis L. is the main source of sesquiterpene ferutinin, a bioactive compound studied both in vitro and in vivo, because of different effects, such as phytoestrogenic, antioxidant, anti-inflammatory, but also antiproliferative and cytotoxic activity, performed in a dose-dependent and cell-dependent way. The present review will focus on the molecular mechanisms involved in the different activities of Ferutinin, starting from its antioxidant potential at low doses until its ionophoric property and the subsequent mitochondrial dysfunction induced through administration of high doses, which represent the key point of its anticancer action. Furthermore, we will summarize the data acquired from some experimental studies on different cell types and on several diseases. The results obtained showed an important antioxidant and phytoestrogenic regulation with lack of typical side effects related to estrogenic therapy. The preferential cell death induction for tumor cell lines suggests that ferutinin may have anti-neoplastic properties, and may be used as an antiproliferative and cytotoxic agent in an estrogen dependent and independent manner. Nevertheless, more data are needed to clearly understand the effect of ferutinin in animals before using it as a phytoestrogen or anticancer drug.

The essential oils obtained by the hydrodistillation from the fresh flowers, leaves, stems, and roots of Ferula communis L., growing in Tunisia were analyzed by GC and GC/MS. Thirty-two components were identified in the oil of flowers with camphor (18.3 %), α-pinene (15.3 %), and β-eudesmol (9.3 %) as the main constituents. Twenty-nine compounds were identified in the oil of stems with β-eudesmol (28.1 %), δ-eudesmol (11.1 %), and α-eudesmol (9.6 %) as the main compounds. Twenty compounds were characterized in the oil of roots with dillapiole (7.9 %), guaiol (7.3 %), and spathulenol (6.8 %). In the oil of leaves, α-eudesmol (25.2 %), β-eudesmol (20.7 %), δ-eudesmol (10.1 %), and caryophyllene oxide (7.2 %) were found as the main constituents. This study was undertaken to evaluate the antioxidant activity using DPPH (2,2′-diphenyl-1-picrylhydrazyl), ABTS (2,2′-azinobis-3-ethylbenzothiazoline-6-sulfonic acid), reducing power, and catalase activity. We tested also the antibacterial, cytotoxic, and cholinesterase inhibition properties of the essential oil of different organs of F. communis. The essential oil of the stems showed the highest antioxidant activity (IC50 = 0.03 ± 0.001 mg mL−1), in DPPH assay and the important result of catalase (303.03 µmol H2O2 degraded/min/protein) of F. communis. The antibacterial activity of the oil was determined by micro-well dilution assay. The best results (MIC = 0.156 ± 0.02 mg mL−1) were exhibited by the essential oil of the leaves of F. Communis against Pseudomonas aeruginosa. Besides, the strongest cytotoxic activity against Hela cells was shown with essential oils’ leaves with an inhibition percentage of 79.05 % at the concentration of 500 µg mL−1. However, the best inhibition percentage of A 549 cells was detected for essential oils’ leaves with an inhibition percentage of 54.56 % at 250 µg mL−1. Our finding showed that the essential oil of the flowers was the most active, with 64.623 % of inhibition against butyrylcholinesterase at 10 mg mL−1 from the incubation time of 30 min.

Species of the genus Laserpitium have been used traditionally to treat inflammation and infection. From the herb of Laserpitium zernyi, six new compounds were isolated and their structures elucidated (using IR, NMR, HRMS data) a derivatives of 8-daucene,2,4,10-triol (1, 2, and 4), 7-daucene-2,4,10-triol (3), a lapiferin derivative featuring a C-2 ester moiety (5), and a daucane featuring an exomethylene group at C-8 (6). Also isolated were the rare daucanes vaginatin (7) and laserpitin (8). In a search for selective glucocorticoid receptor (GR) modulators, the compounds were tested for their capacity to inhibit NF-kappa B and AP-1 pro-inflammatory factors and for a potential competitive effect on a dexamethasone (Dex)-induced GR-driven glucocorticoid response element (GRE) reporter gene. The new 2 beta-angeloyloxy-10 alpha-acetoxy-8-daucene-2,4,10-triol (2) significantly inhibited transactivation of both NF-kappa B and AP-1, while vaginatin (7) was the most active of the compounds tested in blocking AP-1, Both compounds competitively repressed Dex-induced GRE-driven promoter activities, indicative of a potential role for GR. In addition, a decreased potential to inhibit NF-kappa B was apparent in GR knockout A549 cells. In line with the transcriptional assays, compounds 2 and 7 also significantly lowered CCL-2 chemokine production, albeit to a lesser extent than Dex. The results suggest that daucanes may be interesting candidates in the search for compounds with GR-modulating activities.

Seventeen Maltese propolis samples were studied by GC–MS after silylation. They exhibited the typical Mediterranean chemical profile, rich in diterpene compounds (18–92% of TIC, GC–MS): 32 individual diterpenes were identified; 22 of them were present in each specimen. The other abundant compound group was that of sugars and sugar derivatives. In some samples, however, another compound group was observed (0–12% of TIC, GC–MS); the corresponding mass spectra were consistent with mono- and sesquiterpenyl esters of substituted benzoic acids. Two new propolis constituents of this group, daucane diterpene esters of hydroxybenzoic acids, were isolated. Their origin is suggested to be Ferula communis, as they are taxonomic markers for this species. All propolis samples were active against Staphylococcus aureus but only those with high concentrations of terpenyl esters showed antifungal activity against Candida albicans. The present results confirm that Mediterranean propolis is a valuable natural product with potential to improve human health., peer-reviewed

F. communis and D. viscosa are perennial Mediterranean weeds that have been used for different therapeutic purposes in traditional pharmacopeia. Plant extracts were obtained from air dried D. viscosa young shoots (DvA) and F. communis aerial part (FcA) and roots (FcR) with n-hexane. The chemical compositions of the extracts were analyzed by HPLC-DAD, LC-MS (ESI) and LC-Q-TOF techniques. Two sesquiterpene lactones (inuviscolide, tomentosin) and three sesquiterpene acids (costic acid, hydroxycostic acid, ilicic acid) were identified from the D. viscosa extract, while in F. communis extracts three daucane sesquiterpenes (acetoxyferutinin, oxojaeskeanadioyl anisate, fertidin) and one coumarin (ferulenol) derivates were found. Biological activities of plant extracts were studied in in vitro experiments on the colonies and conidia of Botryotinia fuckeliana, Penicillium digitatum, P. expansum, Monilinia laxa, M. fructigena and Aspergillus spp. Extracts showed varying degree of antifungal activities on colony growth and conidia germination. The extract from FcA showed the least effect, while DvA extract had the strongest fungitoxic effects. FcR extract presented a fungitoxic effect on the colony growth, but it was not able to inhibit the conidia germination. These distinctions can be attributed to the differences in chemical composition of plant extracts.

We synthesized several sulfur isosters of ferulenol and related prenylcoumarins from Ferula communis preliminary to finding whether the antitubercular activity of these natural compounds might be dissociated from their antithrombin activity. Direct thionation of ferprenine, an instance of “diversity-oriented” synthesis, yielded a mixture of three thiocoumarin derivatives. When 4-hydroxy-2-deoxy-2-thiocoumarin was reacted with farnesal and other α,β-unsaturated aldehydes, the isosteric oxygen-sulfur substitution at position 2 surprisingly caused a regiochemical inversion in the tandem Knoevenagel-electrocyclic reaction, prevalently affording the linear adduct. An extensive investigation with variously substituted enals highlighted a competition between Knoevenagel and Michael addition. This result was rationalized by energy calculations that took into consideration steric and electronic factors as well as complex formation with the catalyst.

The enantiomer of (+)-allohedycaryol, a germacrane alcohol isolated from giant fennel (Ferula communis L.), has been synthesized, thereby elucidating the relative and absolute stereochemistry of the natural product. The synthesis of (-)-allohedycaryol started from (+)-alpha-cyperone (5) which was available in relatively large quantities via alkylation of imine 7 derived from (+)-dihydrocarvone and (R)-(+)-1-phenylethylamine. In a number of steps 5 was converted into the mesylate 4with a regio- and stereoselective epoxidation as the key step. A Marshall fragmentation of 4 was used to prepare the trans,trans-cyclodeca-1,6-diene ring present in allohedycaryol. The conformation of synthetic (-)-allohedycaryol was elucidated via photochemical conversion into a bourbonane system. The synthesis of (-)-allohedycaryol also showed that natural (+)-allohedycaryol has the opposite absolute stereochemistry to that normally found in higher plants.

Plants of the genera Ferula and Ferulago are known for their complex content in bioactive secondary metabolites such as coumarins, phenylpropanoids, and sesquiterpenes. We used the ground parts of Ferula communis subsp. communis, Ferula glauca subsp. glauca and Ferulago campestris as natural sources for the isolation of four coumarins (CU-1 to CU-4), two phenylpropanoids (PE-1 and PE-2), one polyacetylene (PA-1) and 16 daucane esters (DE-1 to DE-16). The cytotoxic activity of the isolated compounds was evaluated against a panel of seven human tumor cell lines. Fourteen of the daucane derivatives showed antiproliferative activity at least against one of the human tumor cell lines tested, four compounds (DE-5, DE-8, DE-11, and DE-16) were active against all the tested cell lines. Among them DE-11 was the most cytotoxic compound against HeLa (4.4 ± 0.7 μM), A549 (2.8 ± 1.4 μM), HL-60 (2.6 ± 0.4 μM), K562 (26.5 ± 6.0 μM) RS 4;11 (1.7 ± 0.3 μM) and SEM (2.4 ± 0.1 μM) cell lines, while DE-8 was the most active against Jurkat (3.3 ± 0.8 μM). Preliminary structure-activity relationship suggests that the most active compounds in the daucane series present the trans fusion of the penta- and hepta-atomic cycles, and lipophylic ester groups linked to position 6. Isomeric derivatives such as DE-8 and DE-9 or DE-3, DE-4, and DE-5 exhibited significant differences in their IC(50) supporting that the β orientation for the ester group in the position 2 enhances the cytotoxic activity. Furthermore, the pro-apoptotic effect of the most active compounds evaluated in Jurkat cell line showed that these compounds are able to induce apoptosis in a time and concentration-dependent manner. Our findings suggest the potential role of daucane derivatives as models for the development of proapoptotic compounds.

The roots of the nonpoisonous chemotype of giant fennel (Ferula communis) from Sardinia afforded a novel cadinanetriol (1), whose structure was established by spectroscopic data and confirmed by synthesis from the E,E-Delta (1(10),5) germacradiene allohedycariol. A number of known compounds were also identified. Despite the lack of morphological differences, a broad chemical diversity exists within giant fennel, underlying the contrasting data on its poisonous properties.

The fruits of the toxic variety of Ferula communis gave a series of 1-oxojaeskeanadiol esters, whose structure was established by spectroscopic data and chemical reactions, including correlation with jaeskeanadiol. Treatment of these esters with potassium hydroxide gave two polienonic products, resulting from the stepwise elimination of the ester group and one water molecule. Both compounds were unstable; the dienone underwent rapid deconjugation via a 1,5-sigmatropic hydrogen shift, whereas the trienone was oxidized in air at the terminal bond of the conjugated system. The toxic prenylated coumarins were not found in the fruits.

In addition to the known sesquiterpene-coumarin samarcandin and two known phenylpropanoids, two new cyclic farnesyl-coumarin and two new cyclic farnesyl-chromone derivatives were isolated from the benzene extract of the roots of Ferula communis subsp. communis. Structures of the new compounds were elucidated by spectral methods.

The structure of a new prenylated coumarin (E-omega-benzoyloxyferulenol, 1b) from the Sardinian giant fennel (Ferula communis) has been confirmed by synthesis. The parent compound ferulenol (1a) showed sub-micromolar antimycobacterial activity, which was partly retained in 1b and in the simplified synthetic analogue 3, but diminished in its omega-hydroxy and omega-acetoxy derivatives (1c and 1d, respectively). The outstanding activity of 1a, its low toxicity, and the evidence for definite structure-activity relationships make this prenylated 4-hydroxycoumarin an interesting antibacterial chemotype worth further investigation.

A new 4-hydroxycoumarin, isoferprenin {1}, has been isolated from Ferula communis var. genuina and its structure elucidated from spectroscopic studies including ir, ms, and nmr

Fourteen daucane esters together with a known propiophenone 3,4-methylenedioxy-5-hydroxy-propiophenone, were isolated from Ferula communis subsp. communis . Except for the 6-( p -anisic acid) ester of jaeschkeanadiol all these esters are new. Structures were elucidated using spectral properties of the esters and their partial hydrolysis products. X-ray diffraction analysis of one of the compounds confirmed its structure including the stereochemical assignments made on the basis of spectral data.

From the latex of Ferula communis , two 4-hydroxycoumarin derivatives were isolated bearing a farnesylic and a 12-hydroxyfarnesylic residue, respectively, at C-3. Prenylated coumarins, which represent toxic principles of the plant, were absent in other samples, which gave, besides known compounds, a germacrane alcohol (hallohedycariol) and a daucane ester (siol p -hydroxybenzoate).

From the toxic variety of Ferula communis, derivatives of the prenylated coumarins ferulenol and ferprenin bearing an oxygen function (hydroxyl, acetoxyl, aldehydic carbonyl) at the ω-composition have been isolated. The structures of the coumarins were established by spectral methods and by chemical reactions. Photooxygenation of ferulenol and (E) ω-hydroxyferulenol gave o-hydroxyphenylglyoxylic esters, resulting from the oxidative decarbonylation of the 4-hydroxycoumarinic nucleus and loss of the prenyl side chain. Ethyl o-hydroxyphenylglyoxylate was also isolated from the plant extract, suggesting that a reaction of this type might be responsible for the degradation of the prenylated coumarins in plant samples and extracts of Ferula communis.

Together with the known daucene ester 14- p -anisoyloxy-dauc-4,8-diene, a new ester, fercomin and the first known daucane-γ-lactone, fercolide, were isolated from Ferula communis subsp. communis . Structures for these compounds were elucidated on the basis of their spectral properties and the structure of fercomin was confirmed by X-ray analysis. A revised structure of vaginatin is discussed.

The benzene extract from the roots of FERULA COMMUNIS afforded the coumarin ferulenol ( 1) and the structurally related acetylenes named ferulinolone [3-(1,2-dihydrofalcarinolonyl)-ferulenol] ( 4) and decarboxyferulinolone [2-nor-3-(1,2-dihydrofal-carinolonyl-ferulenol] ( 7). The structures of these substances were deduced from their spectral data and those of their derivatives, mainly from the (1)H- and (13)C-NMR 1D and 2D spectra (one bond and long-range correlations). Methoxylatifolone ( 10) was also isolated from this extract.