Daucane Esters Research Articles

Study the Effect of Ferula hermonis Extract on HepG2 cell line culture

Ferula hermonis Boiss (Apiaceae) is known in the Midleast as
 "zallouh". In the last decade, scientists paid attention to study
 
 chemistry and biological activity of the plant. In this study Ferula
 hermonis were collected and evaluated for cytotoxic activity. The
 plant was extracted with methanol The cytotoxic effect of the
 extracts was examined in-vitro on human cell line (Human liver
 carcinoma cell line HepG2). Results were shown that significant
 decrease of HepG2 cells viability. The effect of F. hermonis on cell
 viability of HepG2 cell line culture show that plant extract cause
 significant decrease ( p< 0.05) of HepG2 cell viability, and this
 decrease in cell viability is increased with the increasing the extract
 concentrations in comparison with the negative control, and the
 growth inhibition percentage reach to (78.3%).
 Introduction
 
 Ferula hermonis Boiss. (Apiaceae), commonly known as " Shilsh-
 el-zallouh" , "Hashishat-al-kattira" or "The Lebanese Viagra" ,is a
 small perennial shrub that grows abundantly at more than 2500 m on
 the high mountain areas of northern Lebanon, and on the biblical
 Mount Hermon in Southern Lebanon, (El-Taher et al., 2001). Middle
 East herbalists have used the seeds and roots of this plant for
 centuries as a folk remedy as an aphrodisiac to treat frigidity in
 women, and erectile and sexual dysfunction in men by increasing
 blood flow to sexual organs. The antimicrobial activity of the crude
 extract and the isolated compounds has been reported (Hilan et al.,
 2007). Previous phytochemical studies on this plant have revealed
 the presence of various sesquiterpenes, mainly of the daucane ester
 type (Galal et al., 2001). On roots of Ferula hermonis, several
 sesquiterpenes have been isolated, most of which display biological
 activities. The active constituents are believed to be daucane alcohols

Cytotoxic activity of the genus Ferula (Apiaceae) and its bioactive constituents

The genus Ferula L. includes perennial flowering plants belonging to the Apiaceae family. This genus is a rich source of biologically active phytochemicals such as sulfur-containing derivatives, coumarins, sesquiterpenes, sesquiterpene lactones, sesquiterpene coumarins, glucuronic acid, galactose, arabinose, rhamnose, and daucane esters. Over the last decade, considerable attention has been paid to biological activities of these compounds; it is assumed that the most prominent biological features of the genus Ferula are their cytotoxic effects. This article discusses cytotoxic activity of the genus Ferula and their important compounds. In this mini-review article, papers published from 1990 to April 2016 were included and the following information was discussed; cytotoxic activity of the genus Ferula and their important compounds, the type of cell line used in vitro, concentrations of the extracts/active compound that were used, and the underlying mechanisms of action through which Ferula-related chemicals induced cytotoxicity. In addition, we explained different mechanisms of action through which the active constituents isolated from Ferula, could decrease cellular growth. It is highly recommended that potent and effective compounds that were isolated from Ferula plants and found to be appropriate as adjuvant therapy for certain diseases, should be identified. Also, the versatile biological activities of sesquiterpene coumarins suggest them as promising agents with a broad range of biological applications to be used in the future.

Recent Advances on Bioactive Constituents in Ferula.

Preclinical Research The genus Ferula (Umbelliferea) is widely distributed across Central Asia and the Mediterranean. Some plants of the genus Ferula have been used as sources of pharmaceuticals for centuries. Ferula is a rich source of biologically active compounds, including coumarin derivatives, sesquiterpene-substituted compounds, daucane esters, humulane, and germacrane compounds, aromatic lactones and disulfide compounds. Therefore, utilizing these bioactive constituents with antimicrobial and insecticidal effects not only can provide a new strategy for developing drug and green pesticide, but also protect endangered plant resources. In the present review, research advances on the bioactive constituents of the genus Ferula the plant sources. Drug Dev Res 78 : 321-331, 2017. © 2017 Wiley Periodicals, Inc.

Daucane esters from laserwort (Laserpitium latifolium L.) inhibit cytokine and chemokine production in human lung epithelial cells

BackgroundLaserwort, Laserpitium latifolium L. (Apiaceae), is a European medicinal plant. Its roots and rhizomes were traditionally used as a general tonic and to treat inflammatory and infective diseases. PurposeThe anti-inflammatory potential of daucane esters, isolated from underground parts extract of L. latifolium and specific structural features that contribute to their activity were investigated. In addition, we studied their interference with the transactivation capacity of the Glucocorticoid Receptor when added together with a classic glucocorticoid (GC), dexamethasone (DEX). This particular property may be relevant in combination strategies, attempting to circumvent diabetogenic side effects of glucocorticoids upon long-term anti-inflammatory treatments. Materials and methodsNine L. latifolium daucane esters were isolated and elucidated as derivatives of desoxodehydrolaserpitin, laserpitin and a novel 2β-esterified laserpitinol analogue. Of all compounds effects on NF-κB- and AP-1-driven pro-inflammatory pathways were assessed using TNF- or PMA-induced reporter gene analysis in A549 cells. Daucanes with a strong and concentration-dependent inhibition of both NF-κB and AP-1, were tested for a potential effect on DEX-stimulated GR-driven Glucocorticoid Response Element (GRE) reporter gene activity. In addition, GRE-driven anti-inflammatory mRNA expression was determined (GILZ and DUSP1). Also anti-inflammatory properties were validated by monitoring effects on CCL-2, IL-6, IL-1β mRNA expression levels (qPCR) and on CCL-2 chemokine production (ELISA). ResultsDaucanes featuring an ester moiety and/or a hydroxy group at positions 2β, 6α and 10α and especially the novel 2β-esterified laserpitinol derivative that, in comparison to other isolated compounds, features an additional 9α-hydroxy group, demonstrated suppression of both NF-κB- and AP-1-dependent pro-inflammatory pathways. Remarkably, those entities competitively and concentration-dependently repressed GR-driven GRE-dependent reporter gene activities. The most active compounds inhibited CCL-2 protein excretion and compound 4 downregulated genes coding for IL-1β and IL-6 induced upon TNF treatment in A549. In absence of TNF, compound 4 upregulated the GRE-mediated anti-inflammatory gene GILZ, but not DUSP1. ConclusionsDaucane esters are novel anti-inflammatory agents that may, in combination with GCs, potentially improve therapeutic benefit. These results contribute to the ongoing search for novel anti-inflammatory agents as safer alternatives to, or with, GCs.

Comparative inhibitory effect of prenylated coumarins, ferulenol and ferprenin, contained in the ‘poisonous chemotype’ of Ferula communis on mammal liver microsomal VKORC1 activity

Two distinguishable chemotypes of Ferula communis have been described: the ‘nonpoisonous’ chemotype, containing as main constituents the daucane esters; and the ‘poisonous’ chemotype containing prenylated coumarins, such as ferulenol and ferprenin. Ferulenol and ferprenin are 4-oxygenated molecules such as dicoumarol and warfarin, the first developed antivitamin K molecules. Antivitamin K molecules specifically inhibit VKORC1, an enzyme essential for recycling vitamin K. This latest is involved in the activation of clotting factors II, VII, IX, X. The inhibiting effect of ferulenol on VKORC1 was shown in rat, but not for species exposed to F. communis while in vivo studies suggest differences between animal susceptibility to ferulenol. The inhibiting effect of ferprenin on VKORC1 was never demonstrated. The aim of this study was to compare the inhibiting effect of both compounds on VKORC1 of different species exposed to F. communis. Vitamin K epoxide activity was evaluated for each species from liver microsomes and inhibiting effect of ferulenol and ferprenin was characterized. Ferulenol and ferprenin were shown to be able to inhibit VKORC1 from all analyzed species. Nevertheless, susceptibility to ferulenol and ferprenin presented differences between species, suggesting a different susceptibility to ‘poisonous’ chemotypes of F. communis.

Natural daucane esters induces apoptosis in leukaemic cells through ROS production

Continuing our research on antiproliferative agents from plants, we extended our interest on further compounds isolated from Ferula communis and Ferulago campestris. One new daucane (DE-20) and one new phenol derivative (PH-3) were isolated and characterized in addition to six daucane, three coumarins and four simple phenolics. The cytotoxic activity was evaluated against a panel of six human tumor cell lines. The derivative DE-17 that resulted moderately active on all the studied cell lines was studied to evaluate its possible mechanism of action. DE-17 was able to induce apoptosis in a time and concentration-dependent manner in SEM and Jurkat cell lines. We observed that DE-17 just after 1h of treatment increased the reactive oxygen species (ROS) production and that the co-incubation of DE-17 with ROS scavengers significantly increased cell viability suggesting that ROS-mediated downstream signaling is essential for the antiproliferative effects of DE-17. At later times of incubation DE-17 induced mitochondrial depolarization, as well as caspase-3 and -9 activation suggesting that apoptosis follow the mitochondrial pathway. Concomitantly to ROS induction, a remarkable decrease of mRNA expression of several antioxidant enzymes and intracellular GSH content was detected in treated cells compared to controls further indicative of oxidative stress. Taken together our results showed for the first time that daucane esters induces apoptotic cell death through a ROS-mediated mechanism in human leukemia cells.

Natural daucane sesquiterpenes with antiproliferative and proapoptotic activity against human tumor cells

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.

Antiinflammatory sesquiterpenes from the root oil of Ferula hermonis

Ferula hermonis Boiss. (Apiaceae), commonly known as 'Shilsh-el-zallouh', 'Hashishat-al-kattira' or 'The Lebanese viagra', is a small shrub that grows abundantly on the Hermon Mountain between Syria and Lebanon. The seeds and roots of this plant have long been used in the Middle East as an aphrodisiac, and for the treatment of frigidity and impotence for both men and women. The antiinflammatory properties of three major daucane esters, ferutinin (1) teferin (2) and teferidin (3), isolated from the root oil of Ferula hermonis, were assessed by the carrageenan-induced oedema model in rats. The antiinflammatory effect of both 1 and 2 was observed with a dose of 100 mg/kg, while compound 3 did not show any antiinflammatory activity; conversely it produced a significant proinflammatory effect 2 and 3 h after carrageenan injection.

Identification of non-alkaloid acetylcholinesterase inhibitors from Ferulago campestris (Besser) Grecescu (Apiaceae)

Inhibition of Acetylcholinesterase (AChE) is still considered as a strategy for the treatment of neurological disorders such as Alzheimer's disease. Many plant derived alkaloids (such as galantamine and rivastigmine) are known for their AChE inhibitory activity. Recently, other classes of natural compounds such as terpenoids, sesquiterpene glycosides and coumarins have been studied as new AChE inhibitors, with the aim to discover less toxic compounds compared to alkaloidal ones. The Ferulago campestris roots dichloromethane extract was used for a bioassay-guided fractionation for the search of AChE inhibitors. Three coumarin derivatives (umbelliprenin 1, coladonin 2 and coladin 3), three daucane ester derivatives (siol anisate 4, ferutinin 5 and 1-acetyl-5-angeloyl lapiferol 6), two phenol derivatives (2-epilaserine 7 and epielmanticine 8) and one polyacetylene (9-epoxyfalcarindiol 9) were isolated by the bioassay-guided approach. Their structures were characterized on the basis of spectral methods (1D and 2D NMR, and MS spectroscopy). All the isolated compounds were able to inhibit the AChE (IC 50 1.2–0.1 mM) although at higher doses if compared to galantamine (6.7 μM) measured in the same conditions. The most active compounds were the daucane derivative siol anisate 4 and the epielmanticine 8, with IC 50 of 0.172 and 0.175 mM respectively.

Feruhermonins A–C: three daucane esters from the seeds of Ferula hermonis (Apiaceae)

Seventeen daucane esters have been isolated from the seeds of Ferula hermonis Boiss (Apiaceae). Three of these sesquiterpenes, 4β-hydroxy-6α-benzoyl-7-daucen-9-one (1), 4β, 8β-dihydroxy-6α-benzoyl-dauc-9-ene (2), and 4β, 9α-dihydroxy-6α-benzoyl-dauc-7-ene (4), named feruhermonins A–C, respectively, are novel natural products. The structures of these compounds were elucidated unequivocally by a series of 1D and 2D NMR analyses. Although 4β, 8β-dihydroxy-6α-(4-hydroxy-3-methoxybenzoyl)-dauc-9-ene (3) was reported previously, the complete spectroscopic data for this compound are presented here for the first time.

Sesquiterpenoids from Homalomena occulta affect osteoblast proliferation, differentiation and mineralization in vitro

Chemical investigation of rhizomes of Homalomena occulta (Lours) resulted in isolation and identification of two sesquiterpenoids ( 6, 7), and one daucane ester 8, together with five known sesquiterpenoids, oplodiol, oplopanone, homalomenol C, bullatantriol, and 1β,4β,7α-trihydroxyeudesmane. Their structures were elucidated using 1D and 2D NMR spectroscopic and X-ray analyses. The chloroform extract of this plant and compounds 1– 7 were tested in vitro for their activities in stimulating osteoblast (OB) proliferation, differentiation and mineralization. Compounds 1– 4 had a stimulative effect on significantly proliferation and differentiation of culture osteoblasts, while the chloroform extract and 1 significantly stimulated mineralization of cultured osteoblasts in vitro.

Analytical Discrimination of Poisonous and Nonpoisonous Chemotypes of Giant Fennel (Ferula communis L.) through Their Biologically Active and Volatile Fractions

Giant fennel (Ferula communis L.) from Sardinia is characterized by two chemotypes with different biological activities. One chemotype is poisonous, due to prenylcoumarins, and responsible for ferulosis, which mainly affects sheep and goats, cattle, and horses; the other chemotype is nonpoisonous and contains daucane esters. The two chemotypes cannot be distinguished botanically. High-performance liquid chromatography-diode array-ultraviolet detection-mass spectrometry (HPLC-DAD-UV-MS) analysis of the composition of the fractions containing the biologically active metabolites and of the volatile fractions, by gas chromatography-mass spectrometry (GC-MS), of both essential oil and headspace sampled by headspace solid-phase microextraction (HS-SPME) are here shown to be effective in discriminating the poisonous and nonpoisonous chemotypes. HS-SPME with CAR/PDMS/DVB in combination with GC-MS has also been found to be a successful, fully automated one-step method for rapid and unequivocal discrimination of the two chemotypes, using aristolene and allohedycaryol as markers of the poisonous and nonpoisonous chemotypes, respectively.

Rare trisubstituted sesquiterpenes daucanes from the wild Daucus carota

Phytochemical and biological investigation of the roots of the wild Daucus carota ssp. carota afforded three new and four known compounds, including four sesquiterpenes daucane esters ( 1– 3 [new], and 4), one polyacetylene ( 5), one sesquiterpene coumarin ( 6), and sitosterol glucoside. The structures of the new compounds were determined by comprehensive NMR studies, including DEPT, COSY, NOESY, HMQC and HMBC analyses. Based on an agar diffusion assay, 1, 2 and 4– 6 were screened and found to contain a range of low antibacterial activities against four gram positive ( Staphylococcus aureus, Streptomyces scabies, Bacillus subtilus, Bacillus cereus) and two gram negative species ( Pseudomonas aeruginosa, Escherichia coli) as well as antifungal against Fusarium oxysporum and Aspergillus niger using cup agar diffusion assay.

Daucane phytoestrogens: a structure-activity study.

The estrogenic activity of a series of analogues of the daucane ester ferutinin (1a) modified at the acyl moiety was investigated in a yeast screen containing the human estrogen receptor alpha. Rather strict structure-activity relationships were observed. Thus, while the parent polyol (jaeschkeanadiol, 2a) was inactive, the presence of a p-hydroxybenzoyl moiety was necessary for activity in the yeast screen. Homologation and vinylation were both detrimental for activity, as were methylation of the p-hydroxyl substituent and the introduction of oxygen functions on the adjacent carbons.

Sesquiterpenoids from the fruits of Ferula kuhistanica and antibacterial activity of the constituents of F. kuhistanica

Ethyl acetate extracts of the air-dried fruits of Ferula kuhistanica afforded three daucane esters: kuhistanicaol H, I and J, together with nine other known compounds. Their structures were established on the basis of spectroscopic evidence. Isolated compounds in this paper and previously reported compounds from the roots and stems of F. kuhistanica were tested for antibacterial activity. Some of them were selectively toxic against Gram-positive bacteria, including methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA).

Separation and Quantification of the Major Daucane Esters of Ferula hermonis by HPLC

A simple HPLC method was developed to quantify the major daucane sesquiterpene esters present in herb and roots of Ferula hermonis Boiss. The method utilized a C(18) reversed phase analytical column with isocratic elution for 30 minutes and UV detection at 240 nm. Extracts from two crude plant samples and two commercial products were fingerprinted and quantitatively analyzed.

Daucane sesquiterpenes from Ferula hermonis.

The roots of Ferula hermonis Boiss yielded two new daucane esters, 14-(4'-hydroxybenzoyloxy)dauc-4,8-diene (1) and 14-(4'-hydroxy-3'-methoxybenzoyloxy)dauc-4,8-diene (2), together with the four known sesquiterpenes jaeschkeanadiol p-hydroxybenzoate (3), jaeschkeanadiol benzoate (4), jaeschkeanadiol (5), and epoxyjaeschkeanadiol (6). The identities of the isolated compounds were ascertained primarily using NMR and MS data. Compounds 1 and 3 exhibited antimicrobial activity against Staphylococcus aureus with IC(50) 1.5 and 3.5 microg/mL, respectively, and against Methicillin-resistant S. aureus with IC(50) 2.0 and 4.0 microg/mL, respectively.

Sesquiterpenoids from Ferula kuhistanica

Methanol extracts of the air-dried roots and stems of Ferula kuhistanica afforded seven daucane-type sesquiterpenes, called kuhistanicaol A–G, together with 13 known daucane esters. Their structures were established on the basis of spectroscopic evidence and the results of chemical reactions.

Antibacterial constituents from the rhizomes ofFerula communis

The rhizomes of Ferula communis yielded three antibacterial sesquiterpenes, namely, the new daucane ester 14-(o-hydroxycinnamoyloxy)-dauc-4,8-diene (1), ferulenol (2) and ferchromone (3). Compound 1 exhibited significant activity against Gram-positive bacteria, while 3 was found to be less active. Compound 2, on the other hand, demonstrated potent activity against Mycobacterium organisms, and its corresponding C-4-acetoxy derivative 9 was found to retain the same activity as well. In addition, the rhizomes yielded a number of inactive compounds, including 2-nor-1,2-secoferulenol, elemicin, colladonin, feselol and compounds 4 and 5. Structural assignments were largely based on the spectral data, especially the 2D NMR COSY and HETCOR experiments. © 1998 John Wiley & Sons, Ltd.

New Sesquiterpenes from Xanthium catharticum

A new daucane ester, lasidiol p-methoxybenzoate, and the known guaianolide ziniolide were isolated from the roots of Xanthium catharticum. The MeOH extract of the aerial part afforded three new xanthanolides, 11α,13-dihydro-8-epi-xanthatin and the corresponding 1β,5β- and 1α,5α-epoxides, 7 and 8, respectively. The structures were elucidated by highfield nmr techniques. Cytotoxic and antitumor activities were found for ziniolide