Structure-guided isolation of anti-neuroinflammatory sesquiterpene coumarins from Ferula sinkiangensis.

The resin of Ferula sinkiangensis has been traditionally utilized for treating gastrointestinal disorders, inflammation, tumors, various cancers, and alopecia areata. The primary bioactive constituents, sesquiterpene coumarins, have demonstrated notable therapeutic potential against neuroinflammation. In this study, a structure-guided fractionation method was used to isolate nine novel sesquiterpene coumarins from the resin of F. sinkiangensis. These compounds were characterized and structurally elucidated using comprehensive physicochemical and spectroscopic techniques, including calculated electronic circular dichroism (ECD). Anti-neuroinflammatory assays revealed that compounds 2, 3, and 6 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated BV2 microglial cells, with IC50 values ranging from 1.63 to 12.25 µmol·L-1.

Novel hits for autosomal dominated polycystic kidney disease (ADPKD) targeting derived by in silico screening on ZINC-15 natural product database.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic kidney disorder that leads to growth cysts in the kidney, ultimately resulting in loss of function. Currently, no effective drug therapy can be safely used in the clinic. So, looking for effective therapeutic drugs is urgent for treating ADPKD. Our natural product library was prepared based on the ZINC-15 database. Lipinski's rule of five, drug-likeness, and toxicity screening of the designed library were evaluated. Swiss model online server was used for modeling of GANAB target. Finally, docking-based screening against ADPKD targets was done by MOE 2019 software. The top 14 favorable druglike and non-toxic hits were selected for docking studies. Our results showed that compound-10 (ZINC 6073947) as a sesquiterpene coumarin had more negative binding interaction into the active site of PPARG, OXSR1, GANAB, AVPR2, and PC2 with docking scores of -8.22, -7.52, -6.98, -6.61 and -6.05 kcal/mol, respectively, in comparison to Curcumin, as a natural product that is now in phase 4 clinical trial in ADPKD disease, with an affinity of -8.03, -6.42, -6.82, -5.84 and -5.10 kcal/mol, respectively. Furthermore, seven sesquiterpene coumarins similar to compound 10 were generated and docked. Farnesiferol B (16), compared to compound-10, showed binding affinity of -8.16, -6.4, -7.46, -6.92, and -6.11 kcal/mol against the above targets, respectively. Molecular dynamics, which was done on the compound-10 and 16 (Farnesiferol B) in complex with PPARG, GANAB, and AVPR2, showed more negative binding free-energy than Pioglitazone, Miglitol, and Tolvaptan as FDA-approved drugs for each target, respectively.Communicated by Ramaswamy H. Sarma.

Sesquiterpene coumarins from Ferula sinkiangensis and their anti-pancreatic cancer effects.

Eight previously unreported sesquiterpene coumarins, namely (+)- and (-)-ferulasinkian A (1), (-)-fukanefuromarin M (2), (±)-ferulasinkian C (3), (±)-ferulasinkian D (4), ferulasinkian E (5), ferulasinkian F (7), and ferulasinkian G (8), together with two known compounds, (+)-fukanefuromarin M (2) and 7-hydroxyferprenin (6), have been isolated from the roots of Ferula sinkiangensis (Umbelliferae). The structures of all compounds were elucidated by spectroscopic analysis, along with ECD calculations and optical rotation calculations. Compounds 1-6 are dimers consisting of a chain sesquiterpene and a coumarin with an oxygen-containing six-membered ring connected from coumarin C-3 and C-4. Currently, there are only seven such structures reported in the genus Ferula, and their absolute configurations have not yet been determined. Compounds 7-8 are sesquiterpene coumarin derivatives with a chain sesquiterpene connected with coumarin C-4. In the present study, the chiral separation of compounds (±)-1 and (±)-2 was successfully carried out, and the absolute configurations of compounds (±)-1, (±)-2, 5, 7 and 8 were determined. The isolates were evaluated for their cytotoxic activity against human pancreatic cancer cell lines including CFPAC-1, PANC-1, CAPAN-2 and SW 1990. Compounds (+)-1, (-)-1 and 7 exhibited potent cytotoxicity against pancreatic cancer cells with IC50 values ranging from 4.57 ± 0.94 to 14.01 ± 1.03 µM. Furthermore, the primary mechanistic study of (-)-1 demonstrated that it could induce apoptosis in CFPAC-1 cells.

Ferula sinkiangensis (Chou-AWei, Chinese Ferula): Traditional Uses, Phytoconstituents, Biosynthesis, and Pharmacological Activities.

Ferula is the third largest genus of the Apiaceae family, its species are utilized as a remedy for diverse ailments all over the world. F. sinkiangensis K. M. Shen (Chou-AWei, Chinese Ferula) is mainly found in Xin-jiang Uygur Autonomous Region, China. Traditionally, it is utilized for treating various illnesses such as digestive disorders, rheumatoid arthritis, wound infection, baldness, bronchitis, ovarian cysts, intestinal worms, diarrhea, malaria, abdominal mass, cold, measles, and bronchitis. It can produce different classes of metabolites such as sesquiterpene coumarins, steroidal esters, lignans, phenylpropanoids, sesquiterpenes, monoterpenes, coumarins, organic acid glycosides, and sulfur-containing compounds with prominent bioactivities. The objective of this work is to point out the reported data on F. sinkiangensis, including traditional uses, phytoconstituents, biosynthesis, and bioactivities. In the current work, 194 metabolites were reported from F. sinkiangensis in the period from 1987 to the end of 2022. Nevertheless, future work should be directed to conduct in vivo, mechanistic, and clinical assessments of this plant`s metabolites to confirm its safe usage.

Sesquiterpene coumarins isolated from Ferula bungeana and their anti-neuroinflammatory activities.

This is the first study to profile natural sesquiterpene coumarins (SCs) in Ferula bungeana, a medicinal plant of the genus Ferula in China. Eight undescribed sesquiterpene coumarins (1-8), along with six known ones (9-14) were obtained from the whole plant of F. bungeana. These unreported SCs (1-8) enriched the structural diversity of natural SCs, especially these with the hydroxy or carbonyl group at C-7' and a hydroperoxy group at C-7' or C-8'. Compounds (9-14) were reported for the first time from this plant. The in vitro anti-neuroinflammatory activity assay showed that compounds 2 and 9 showed stronger inhibitory effect on nitric oxide (NO) production in lipopolysaccharide (LPS)-induced BV-2 microglia, compared with positive control minocycline, and compounds 5 and 10 showed moderate inhibitory effects.

Metabolic differences of two Ferula species as potential sources of galbanum: An NMR-based metabolomics study.

INTRODUCTION: Ferula gummosa Boiss. and Ferula galbaniflua Boiss. & Buhse (Apiaceae) are two important Iranian plants that are considered as potential sources of galbanum (barijeh). Galbanum is traditionally used for treating different diseases including flatulence and memory impairment. OBJECTIVE: According to a phylogenetic analysis of the nrDNA ITS sequence and the Flora Iranica, F. gummosa has been considered as a synonym of F. galbaniflua. However, F. galbaniflua and F. gummosa grow in two different geographical locations and have different metabolic patterns. Some researchers believe that F. gummosa and F. galbaniflua are two distinct species. To discriminate these species, we compared metabolic profiles of F. gummosa and F. galbaniflua samples. METHODS: 1 H-NMR-based metabolomics analysis was used for classification of F. gummosa and F. galbaniflua samples collected from northeast Iran. The acquired data were analyzed using hierarchical cluster analysis (HCA), partial least squares discriminant analysis (PLS-DA) and orthogonal projection to latent structures discriminant analysis (OPLS-DA). RESULTS: The result showed a clear separation between the two species that may be related to the quantity and diversity of their metabolites. Ferula gummosa had higher mogoltacin levels, while F. galbaniflua had higher feselol levels. Ligupersin A and conferdione were significantly detected in F. gummosa, whereas sterol compounds were significantly detected in F. galbaniflua. CONCLUSION: Our findings indicate that clear metabolomics discrimination of F. gummosa and F. galbaniflua makes their chemotaxonomic classification possible.

Bioactive sesquiterpene coumarins from the resin of Ferula sinkiangensis targeted on over-activation of microglia.

Nine undescribed (1-4, 6-10) sesquiterpene coumarins, together with a new natural one (5) and ten known ones (11-20), were isolated from the low polarity fraction of the 95% ethanol extract of the resin of Ferula sinkiangensis. Their structures were elucidated based on the comprehensive analysis of HRESIMS, 1D and 2D NMR data. The absolute configurations were determined by comparison of experimental and calculated ECD spectra. All the identified SCs were evaluated for their anti-neuroinflammatory activities in LPS-induced BV-2 cells. Ferusingensine G (8) displayed a significant inhibitory effect on nitric oxide (NO) production with an IC50 value of 1.2 µM. The results suggested that natural SCs might be served as potential neuroinflammatory inhibitors.

Selective isolation of sesquiterpene coumarins from asafoetida using dummy molecularly imprinted solid phase extraction method.

Due to the biological features of sesquiterpene coumarins and incomparable interest in therapeutics application of natural products, extraction of sesquiterpene coumarins from asafoetida have gained highly attention. One of the most important problems is removal of sulfur containing compounds which are co-existed with sesquiterpene coumarins. So employment of new methods for selective extraction and cleanup of sesquiterpene coumarins is very substantial. In this study using dummy molecularly imprinting technique, 7-hydroxycoumarin-imprited polymer was synthesized and after evaluation of binding properties of polymers, the optimum one was used as sorbent in solid phase extraction. Afterwards dummy molecularly imprinting solid phase extraction (DMISPE) method was calibrated for simultaneous extraction of galbanic acid, 7-isopentenyloxy coumarin and auraptene from aqueous media before high performance liquid chromatography with UV detector (HPLC-UV) analysis. The recovery was in the range of 68.32%-84.69%, which were in the acceptable range compared to previous works. Finally, the calibrated DMISPE method was used for extraction and cleanup of sesquiterpene coumarins from asafetida plant. The concentration of isosamarcandin, kellerin and farnesiferol in asafoetida extract was obtained 0.8, 2.7, and 5 µg/mL, respectively, using standard addition method.

Effects of ethanolic extract of Ferula gummosa oleo-resin in a rat model of streptozotocin-induced diabetes.

Previous studies have shown that some plants in the genus of Ferula (Apiaceae) have antidiabetic effects. The present work was aimed to evaluate effects of Ferula gummosa oleo-resin in a rat model of streptozotocin-induced diabetes. Male Wistar rats were randomized into five groups (n = 6): normal control, diabetic control, diabetic rats treated with insulin (3 IU/day), and diabetic rats treated with 100 or 400 mg/kg/day of an ethanolic extract of the oleo-resin. After 4 weeks, blood samples were collected for measuring fasting blood glucose (FBG), lipid profile, aspartate aminotransferase, alanine aminotransferase (ALT), alkaline phosphatase, blood urea nitrogen, and creatinine. In addition, levels of lipid peroxidation, thiol groups, and superoxide dismutase (SOD) activity were evaluated in the liver and kidney. At the end of the fourth week, the level of FBG in rats treated with 100 mg/kg of the extract was lower than that in diabetic control rats (273 ± 39 mg/dL vs 471 ± 32 mg/dL). Administration of insulin and the extract had no significant effects on the serum lipids. Insulin and both doses of the extract significantly reduced the activity of ALT. In addition, the extract inhibited lipid peroxidation in the kidney and restored the elevated level of SOD in the liver and kidneys. Ferula gummosa oleo-resin has the potential to prevent or delay the complications of diabetes by inhibiting the progression of hyperglycemia and attenuating oxidative stress-induced damage in the liver and kidneys.

NMR-based metabolomic study of asafoetida.

Asafoetida, an oleo-gum-resin obtained from the exudates of Ferula assa-foetida L. roots, is traditionally used to treat various diseases including asthma, gastrointestinal disorders, and intestinal parasites. On the basis of Iranian traditional medicine, the main source of asafetida is F. assa-foetida roots. In folk medicine, however, different Ferula species have been used as sources of asafoetida. To identify the original asafoetida that possesses medicinal properties, we should compare metabolic profiles of different asafoetida sources which are commonly used for the oleo-gum-resin preparation.1H-NMR based metabolomics was used to obtain metabolic profiles of eight asafoetida oleo-gum-resin samples and forty-six samples of Ferula species roots from two main regions of Iran. The acquired data were analyzed using multivariate principal component analysis (PCA), partial least squares discriminant analysis (PLS-DA), and orthogonal projection to latent structures discriminant analysis (OPLS-DA) to identify the metabolic differences and similarities between the samples. Asafoetida is usually produced from Ferula species of southern and eastern regions of Iran. A clear metabolic differentiation was evident between asafoetida oleo-gum- resin samples from the southern and those of the eastern Iran. The distinguished metabolites, umbelliprenin, farnesiferol B, farnesiferol C, samarcandin and galbanic acid are significantly found in southern samples. Only southern asafoetida is obtained from F. assa-foetida. Asafoetida from eastern region of Iran is obtained from other species of Ferula such as F. alliacea and its metabolic profile is far different from that of southern asafoetida.

Anatolicin, a Highly Potent and Selective Cytotoxic Sesquiterpene Coumarin from the Root Extract of Heptaptera anatolica.

Seven known sesquiterpene coumarins and a new sesquiterpene coumarin, anatolicin (8), were isolated from the dichloromethane extract of the roots of Heptaptera anatolica. Structures of these compounds were elucidated based on their spectral properties. While some of these sesquiterpene coumarins showed modest cytotoxic activity against COLO205, KM12, A498, UO31, and TC32 cancer cell lines, selective cytotoxicity of anatolicin (8) and 14'-acetoxybadrakemin (7) were observed at nanomolar level against the UO31 kidney cancer cell line.

Phytochemistry and pharmacology of Ferula persica Boiss.: A review.

Ferula persica, is the well-known species of the genus Ferula in Iran and has two varieties: persica and latisecta. They have both been extensively used in traditional medicine for a wide range of ailments. A great number of chemical compounds including sesquiterpene coumarins and polysulfides have been isolated from this plant. Fresh plant materials, crude extracts and isolated components of F. persica have shown a wide spectrum of pharmacological properties including anti-pigmentation in Serratia marcescens, cytotoxic, antibacterial, anti-fungal, anti-leishmanial, cancer chemopreventive, reversal of multi-drug resistance, anti-inflammatory and lipoxygenase inhibitory activity. The present review summarizes the data available regarding the chemical constituents and biological activities of F. persica.

Antiprotozoal and Antiglycation Activities of Sesquiterpene Coumarins from Ferula narthex Exudate.

The exudate of Ferula narthex Boiss. (Apiaceae) is widely used in the Indian subcontinent as a spice and because of its health effects. Six sesquiterpene coumarins have been isolated from this exudate: feselol, ligupersin A, asacoumarin A, 8'-O-acetyl-asacoumarin A, 10'R-karatavacinol and 10'R-acetyl-karatavacinol. Based on its use in infectious and diabetic conditions, the isolated constituents were evaluated for antimicrobial and antiglycation activities. Some compounds showed activity against protozoal parasites, asacoumarin A being the most active one against Plasmodium falciparum K1 (IC50 1.3 µM). With regard to antiglycation activity, in the BSA-glucose test, ligupersin A displayed the highest activity (IC50 0.41 mM), being more active than the positive control aminiguanidine (IC50 1.75 mM). In the BSA-MGO assay, the highest activity was shown by 8'-O-acetyl-asacoumarin A (IC50 1.03 mM), being less active than aminoguanidine (IC50 0.15 mM). Hence, the antiglycation activity of the isolated constituents was due to both oxidative and non-oxidative modes of inhibition.

Reversal of P-glycoprotein-mediated multidrug resistance in MCF-7/Adr cancer cells by sesquiterpene coumarins.

In the present study, fifteen sesquiterpene coumarins were isolated and purified from different Ferula species, and were tested for their MDR reversal properties. Enhancement of doxorubicin cytotoxicity in MCF-7/Adr cells (doxorubicin resistant derivatives of MCF-7 cells overexpressing P-gp), when combined with very non-toxic concentrations of the sesquiterpene coumarins (50 µM) including umbelliprenin, farnesiferol B, farnesiferol C and lehmferin, proved significant MDR reversal activity of these coumarins. Flow cytometric efflux assay confirmed that the intracellular accumulation of Rho123 was significantly increased in MCF-7/Adr cells when treated with sesquiterpene coumarins. A deeper insight into the structure-activity relationship of sesquiterpene coumarins revealed that ring-opened drimane-type sesquiterpene coumarins including farnesiferol B, farnesiferol C and lehmferin possessed the best inhibitory effects on P-gp pump efflux and they could be considered as lead scaffolds for further structure modifications.

Drimane-Type Sesquiterpene Coumarins from Ferula gummosa Fruits Enhance Doxorubicin Uptake in Doxorubicin-Resistant Human Breast Cancer Cell Line.

Multidrug resistance (MDR) is the main cause of failure in the chemotherapy of cancer patients. The present study aimed to evaluate the effects of sesquiterpene coumarins of Ferula gummosa fruits on P-glycoprotein (P-gp)-mediated MDR. Drimane-type sesquiterpene coumarins from the fruits of F. gummosa were extracted with dichloromethane and subjected to column chromatography. The effects of the isolated compounds on P-gp-mediated MDR were evaluated in the breast cancer cell line MCF-7 which shows high resistance to doxoribicin (MCF-7/Dox). Phytochemical investigation of dichloromethane extract of F. gummosa fruits resulted in three sesquiterpene coumarins including conferone (1), mogoltacin (2), and feselol (3). The structures of these compounds were confirmed by 1D and 2D Nuclear Magnetic Resonance (NMR) spectroscopy. Exposure of cells to conferone, mogoltacin, feselol, and verapamil (positive control) enhanced doxorubicin uptake by MCF-7/Dox cells. This effect was dose dependent, but varied with the structure of the chemical. At 25 µM, all the tested sesquiterpene coumarins restored at least 50% of the reference uptake (uptake by sensitive cells); but at 10 µM, their potency varied where conferone showed the highest potency and feselol showed the lowest potency. Conferone, mogoltacin, and feselol from F. gummosa suppress P-gp-mediated drug efflux in highly resistant human breast cancer cells.