Linear Furocoumarins Research Articles

Biosynthetic pathway analysis combined with feature-based molecular networking to comprehensively characterize the chemical constituents in seeds of Sterculia lychnophora.

The seeds of Sterculia lychnophora Hance, commonly known as Pangdahai (PDH) in Chinese, have found extensive use in both culinary and traditional medicinal practices. However, a comprehensive understanding of the chemical composition of PDH has been lacking. This study proposes a strategy that integrates biosynthetic pathway analysis with feature-based molecular networking (FBMN), aiming for a thorough and global characterization of the chemical compositions of PDH. The FBMN map reveals potential compounds with structural similarity, and the MS/MS fragments could be annotated based on library matches, which could predict the plausible biosynthetic pathways in PDH, accomplishing the annotation of compounds clustered in FBMN by integrating biosynthetic pathways. Consequently, 126 compounds were plausibly or unambiguously identified, including 37 phenolic acids and glycosides, 20 flavonoids and glycosides, 12 procyanidins, 21 alkaloids, 22 lipids, and 14 others. Leveraging the information, 40 compounds, including 1 unique isoquinoline alkaloid and 2 rare linear furocoumarins, were isolated and confirmed. This study not only demonstrates a highly effective approach for identifying compounds within complex herbal mixtures but also establishes a robust foundation for the further development of PDH.

Xanthotoxol relieves itch in mice via suppressing spinal GRP/GRPR signaling

Although pruritus, commonly known as itch, is a common and debilitating symptom associated with various skin conditions, there is a lack of effective therapies available. Xanthotoxol (XAN), a biologically active linear furocoumarin, shows potential in the treatment of various neurological disorders. In this study, we discovered that administering XAN either through intraperitoneal or intrathecal injections effectively reduced scratching behavior induced by compound 48/80 or chloroquine. Importantly, XAN also substantially alleviates chronic itch in dry skin and allergic contact dermatitis mice. Substantial progress has highlighted the crucial role of gastrin-releasing peptide (GRP)-gastrin-releasing peptide receptor (GRPR) signaling in the dorsal spinal cord in transmitting various types of itch. Our behavior tests revealed that XAN significantly alleviated scratching behaviors induced by intrathecal administration of GRP or GRPR agonist bombesin. Furthermore, XAN reduced the activation of neurons in the spinal cord caused by intrathecal administration of GRP in mice. Moreover, XAN attenuates the activation of spinal GRPR-positive neurons in itchy mice. These findings suggest that XAN mitigates itch in mice by suppressing spinal GRP/GRPR signaling, thereby establishing XAN as a promising therapeutic option for treating pruritus.

The Simultaneous Determination of Nine Furocoumarins in Angelica dahurica Using UPLC Combined with the QAMS Approach and Novel Health Risk Assessment Based on the Toxic Equivalency Factor

Objective: This study aimed to provide data for the type and content of linear furocoumarins (FCs) in Angelica dahurica (AD) in order to assess their cumulative risks and provide a scientific basis for the rational use and quality evaluation of the medicinal AD to improve public health. Methods: A UPLC method was developed for the simultaneous determination of nine FCs initially by using imperatorin (Im) as the internal standard substance, including Im, phellopterin (Ph), isoimperatorin (Is), oxypeucedanin hydrate (Oh), byakangelicin (Bn), xanthotoxin (8-MOP), bergapten (5-MOP), byakangelicol (Bl), and oxypeucedanin (Op) in two species of Angelica dahurica (AD). And, the risk assessment for the total FCs in AD was explored using the hazard index combined with the toxic equivalency factor (TEF-HI) strategy for the first time. Results: The established method revealed acceptable applicability, and there were no significant differences compared with the external standard method (ESM). The quantitative results demonstrated that the total content of FCs in Angelica dahurica (BZ) were higher than that in Angelica dahurica var. formosana (HBZ), and there was a great difference between the Bl and Op. Moreover, the risk assessment data revealed that the risk of total FCs in AD to human health was low. Conclusions: The established UPLC method that determined nine FCs in AD using a single marker could solve the problem of difficulty in obtaining a chemical reference substance with high purity and requiring a long determination time. And, the TEF-HI risk assessment approach associated with FCs in ADs could guide the rational utilization of toxic FCs in ADs in the progress of improving public health safety. In short, the whole systematic strategy provides a scientific basis for rational quality evaluation and the healthy use of related herbal medicines.

A new coumarin derivative from the roots of Peucedanum praeruptorum Dunn

A phytochemical study on the roots of Peucedanum praeruptorum Dunn yielded 13 compounds, including ten angular pyranocoumarins (1–10), two linear furocoumarins (11 and 12), and a phenolic acid derivative (13). Structural elucidation of the isolated compounds was done by spectroscopic analysis. Compound 1 was a new angular pyranocoumarin derivative, while compounds 12 and 13 were firstly discovered from P. praeruptorum. Moreover, the chemotaxonomic significance corresponding to these isolated compounds was discussed herein.

A Novel Furocoumarin Derivative, 5-((diethylamino)me-13 thyl)-3-phenyl-7H-furo [3,2-g] chromen-7-one Upregulates Melanin Synthesis via the Activation of cAMP/PKA and MAPKs Signal Pathway: In Vitro and In Vivo Study.

Psoralen, a major furocoumarin component of the Fructus Psoralen (FP), in combination with ultraviolet radiation, cures abnormal pigmentation disorder. In a previous study, we synthesized a series of linear furocoumarins with different substituents, out of which 5-((diethylamino)methyl)-3-phenyl-7H-furo [3,2-g] chromen-7-one (encoded as 5D3PC) showed better pigmenting effect than others in B16 cells. In this study, we examined the mechanism underlying the melanogenic effect of 5D3PC both in vivo and in vitro. To examine the pigmentation effect, the B16 and human melanocyte cell lines, PIG1 and PIG3V melanocytes were incubated with 5D3PC. In animal experiments, C57BL/6 mice received 5% hydroquinone and were administrated with 5D3PC for 30 days. 5D3PC upregulated the melanin synthesis and tyrosinase in B16 cell, PIG1 and PIG3V. The expression level of tyrosinase (TYR), tyrosinase-related protein-1 (TRP-1) and tyrosinase-related protein-2 (TRP-2), microphthalmia-associated transcription factor (MITF), cyclic adenosine monophosphate (cAMP), phosphorylation of cAMP-responsive element binding protein (p-CREB), phosphorylation of p38 mitogen-activated protein kinase (MAPK), c- phosphorylation of Jun N-terminal kinase (p-JNK) was significantly higher in 5D3PC-treated B16 cells. The oral administration of 5D3PC attenuated the depigmentation of the C57BL/6 vitiligo mice model by increasing the numbers of melanin-containing hair follicles, melanogenic protein, and melanogenesis-relative genes expression in skin tissues.

Notopterol Attenuates Monocrotaline-Induced Pulmonary Arterial Hypertension in Rat.

IntroductionCurrent targeted pulmonary arterial hypertension (PAH) therapies have improved lung hemodynamics, cardiac function, and quality of life; however, none of these have reversed the ongoing remodeling of blood vessels. Considering notopterol, a linear furocoumarin extracted from the root of traditional Chinese medicine Qiang-Huo (Notopterygium incisum), had shown the antiproliferative and anti-inflammatory properties in previous studies, we hypothesized that it could play a role in ameliorating PAH.MethodsIn vivo, we conducted monocrotaline (MCT) induced PAH rats and treated them with notopterol for 3 weeks. Then, the rats were examined by echocardiography and RV catheterization. The heart and lung specimens were harvested for the detection of gross examination, histological examination and expression of inflammatory molecules. In vitro, human pulmonary arterial smooth muscle cells (HPASMCs) were treated with notopterol after hypoxia; then, cell proliferation was assessed by cell counting kit-8 and Edu assay, and cell migration was detected by wound healing assays.ResultsWe found that notopterol improved mortality rate and RV function while reducing right ventricular systolic pressure in MCT-induced PAH rats. Furthermore, notopterol reduced right ventricular hypertrophy and fibrosis, and it also eased pulmonary vascular remodeling and MCT-induced muscularization. In addition, notopterol attenuated the pro-inflammatory factor (IL-1β, IL-6) and PCNA in the lungs of PAH rats. For the cultured HPASMCs subjected to hypoxia, we found that notopterol can inhibit the proliferation and migration of HPASMCs.ConclusionOur studies show that notopterol exerts anti-inflammatory and anti-proliferative effects in the pulmonary arteries, which may contribute to prevention of PAH.

Chemical constituents from the roots of Peucedanum praeruptorum Dunn and their chemotaxonomic significance

Chemical investigation on the roots of Peucedanum praeruptorum Dunn afforded 15 compounds, including five linear furocoumarins (1–5), six angular pyranocoumarins (6–11), two simple coumarins (12 and 13), a benzaldehyde derivative (14), and a phenylpropanoid glycoside (15). The structures of these compounds were established via spectroscopic analysis and comparison of their NMR data with the literature. Compound 1 was a new linear furocoumarin glycoside, while compounds 10–12, 14 and 15 were isolated from P. praeruptorum for the first time. The chemotaxonomic significance of these isolated compounds was summarized herein.

Coumarins from Magydaris pastinacea as inhibitors of the tumour-associated carbonic anhydrases IX and XII: isolation, biological studies and in silico evaluation

In an in vitro screening for human carbonic anhydrase (hCA) inhibiting agents from higher plants, the petroleum ether and ethyl acetate extracts of Magydaris pastinacea seeds selectively inhibited hCA IX and hCA XII isoforms. The phytochemical investigation of the extracts led to the isolation of ten linear furocoumarins (1–10), four simple coumarins (12–15) and a new angular dihydrofurocoumarin (11). The structures of the isolated compounds were elucidated based on 1 D and 2 D NMR, MS, and ECD data analysis. All isolated compounds were inactive towards the ubiquitous cytosolic isoform hCA I and II (K i > 10,000 nM) while they were significantly active against the tumour-associated isoforms hCA IX and XII. Umbelliprenin was the most potent coumarin inhibiting hCA XII isoform with a K i of 5.7 nM. The cytotoxicity of the most interesting compounds on HeLa cancer cells was also investigated.

Synthetically modified methoxsalen for enhanced cytotoxicity in light and dark reactions

Linear furocoumarins, also known as psoralens, are clinically useful photo-activated pharmaceuticals employed to address hyperproliferative skin diseases. Seven diverse cytotoxic pharmacophores have been synthetically attached to 8-methoxypsoralen via a 5-amino functionality. The resulting unique set of compounds was evaluated for dark and light toxicity against PAM212 keratinocytes in culture.

Notopterygium incisum extract and associated secondary metabolites inhibit apple fruit fungal pathogens

In the search for antifungal lead compounds from natural resources, Notopterygium incisum, a medicine plant only distributed in China, showed antifungal potential against apple fruit pathogens. Based on the bioassay-guided isolation, chromatography fraction 6 of the ethyl acetate partition exhibited significant in vitro and in vivo antifungal activities against apple fruit pathogens. Furthermore, nine antifungal secondary metabolites, including five linear furocoumarins (1–5), two phenylethyl esters (6–7), one falcarindiol (8), and one sesquiterpenoid (9), were isolated and elucidated from fraction 6. Compound 5 is a new metabolite, and 9 isolated from the genus Notopterygium for the first time. The purified compounds (1–9) were firstly reported to exhibit antifungal activities against apple fruit pathogens of Colletotrichum gloeosporioides and Botryosphaeria dothidea with the MIC values ranging from 8 to 250 mg L−1, especially 8 of 16 and 8 mg L−1, respectively. Moreover, 8 could inhibit the spore germination and new sporulation of B. dothidea, as well as enhance the membrane permeabilization of B. dothidea spores. This was the first investigation for the antifungal components against apple fruit pathogens from Notopterygium incisum, which has great potential to be developed into bio-fungicides.

Rapid Access to Oxazine Fused Furocoumarins and in vivo and in silico Studies of theirs Biological Activity.

The synthesis of 1,2-oxazine-fused linear furocoumarins was performed involving the transition metal catalysis reaction of plant coumarin oreoselone derivatives. The Pd-catalyzed desulfonative cross-coupling reactions of 2-(tosyl)oreoselone with terminal alkynes and the successive treatment of the obtained 2-(arylethynyl)furocoumarins with an excess of hydroxylamine gave the expected (Z,E)-3-(hydroxyimino)-2-(arylethynyl)furocoumarins with an (Z:E) ratio of about 1:0.5. The gold(III)-catalyzed cycloisomerization of furocoumarin β,γ-acetylenic (Z)-oximes led to a new group of heterocyclic compounds - chromeno[6',7':4,5]furo[3,2-c][1,2]oxazine. The (E)-isomer in this condition was transformed into (E)-3-(hydroxyimino)-2-(propan-2-ylidene) furocoumarin. Pharmacological screening of the synthesized 1,2-oxazine-fused linear furocoumarins for anti-inflammatory and analgesic activity in vivo revealed that this compounds possessed high activity which was depend on the substitution in the aromatic ring of the oxazine unit. The results of experimental studies were found to be in accordance with that of the in silico docking results. The moderate toxicity of compounds (LD50 value was more than 2000 mg/kg) encouraged the further design of therapeutically relevant analogues based on this novel type of fused linear furocoumarins.

Two nematicidal furocoumarins from Ficus carica L. leaves and their physiological effects on pine wood nematode (Bursaphelenchus xylophilus)

The ethanol extract of the Ficus carica L. leaves was tested to show strong nematicidal activity against pine wood nematode (PWN), Bursaphelenchus xylophilus, causing 90.93% corrected mortality within 72 h at 1.0 mg/mL. From the ethyl acetate soluble fraction of the F. carica L. leaves extract, the main nematicidal constituents were obtained by bioassay-guided isolation and identified as linear furocoumarins bergapten (1) and psoralen (2) by mass and NMR spectral data analysis. Bergapten and psoralen had significant nematicidal activity against PWN with the LC50 values of 97.08 aKSnd 115.03 μg/mL within 72 h, respectively. The two furocoumarins could inhibit the activities of amylase, cellulase and acetylcholinesterase (AchE) from PWN. The morphologies of PWNs changed much after they were treated by bergapten and psoralen. The physiological effects of bergapten and psoralen on PWN might provide helpful clues to elucidate their nematicidal mechanisms.

ChemInform Abstract: Modification of Biologically Active Plant Metabolites via the Transition Metal Catalyzed Reactions

AbstractReview: 44 refs.

Coumarins of Angelica deccurens

It was shown that the plant Angelica deccurens (Ldb.) B. Fedtsch might be serve as a source of valuable coumarins. Five linear furocoumarins – umbelliferon, isoimperatorin, imperatorin, psoralen and oxypeucedanin have been isolated from the roots of Angelica deccurens (Ldb.) B. Fedtsch growing in Mongolia. Molecular structures of these compounds were elucidated by spectroscopic methods. The coumarin psoralen has been isolated for the first time from this plant. DOI: http://dx.doi.org/10.5564/mjc.v14i0.193 Mongolian Journal of Chemistry 14 (40), 2013, p25-27

Coumarins of Peucedanum baicalense and cytotoxic activity of some isolated coumarins

DOI: http://dx.doi.org/10.5564/mjc.v13i0.155 Mongolian Journal of Chemistry Vol.13 2012: 23-27

Possibility of intramolecular hydrogen bonds in 8-methoxypsoralene

Variants of the formation of weak intramolecular hydrogen bonds of C-H…O type in 8-methox-ypsoralene (8-MOP) were considered. Quantum-chemical calculations showed the possibility of an intramolecular hydrogen bond between the protons of the methoxy group and both (furan and pyrone) neighboring oxygen atoms of the psoralene system. The energy gain of this binding was detected by DFT, but not found by the Hartree-Fock method. The bond with pyrone oxygen is energetically more favorable, though the difference in energy between the two types of minima found on PES was small. This interaction had earlier been recorded for linear 8-substituted furocoumarins other than 8-MOP. The conclusion was drawn that the calculated energy barriers on the PES of methoxy group rotation were small enough (2.5 kcal/mol in the Hartree-Fock method, 1.1 kcal/mol in PBE, and 0.9 kcal/mol in B3LYP) to state that the methoxy group rotates freely, creating a steric hindrance for two close-lying oxygens of the psoralene structure, which are not involved in lone electron pair-π system interactions.

Modification of Biologically Active Plant Metabolites Via the Transition Metal Catalyzed Reactions

Developed by the author’s research laboratory methods of functionalization of some plant metabolites or their derivatives, viz., the eudesmane-type methylenelactones, diterpene and morphinane alkaloids, furanolabdanoids, and coumarins, using the transition metal catalyzed reactions, are reviewed. The activity<br />of linear methylene lactone of the eudesmane type in the Heck reaction are analyzed. It is shown that the outcome of the Heck reaction is significantly influenced by the structure of methylidenelactone. The Pd-catalyzed arylation of isoalantolactone with arylhalogenides or 6-bromodeoxyvasicinone occurred with<br />formation mainly of cross-coupling products with the (E) - configuration of the double bond. Synthesis of halogen derivatives of lappaconitine, tetrahydrothebaine and dihydrothebaine-hydroquinone and investigation of in the Heck or Sonogashira reactions gave the possibility for obtaining of new alkaloid derivatives with additional substituents in the aromatic rings. Homocoupling reaction or Sonogashira crosscoupling reaction of 5´- ethynyllappaconitine are used for synthesis of dimeric alkaloids of aconitane types. Pd-catalyzed amination of 2-(1,3-dibromoprop-2-ylidene)oreoselone and the transformations of oreoselone triflate, upon the action of palladium compounds allowed us to accomplish new modifications of linear furocoumarins. The method of enyne cycloisomerization of <em>ω</em>-alkynylfurans catalyzed with Au(III) was successfully obtained in the transformations of furanolabdanoids. The copper(I) salts catalyzed 1,3-dipolar cycloaddition reaction of azides to terminal alkynes belongs to the group of click-reactions was used in the synthesis of macrocyclic structures of labdane diterpenoids. The copper-catalyzed 1,3-dipolar cycloaddition reaction of 2 - azidooreoselone with various alkynes yielded diverse 2-(1,2,3-triazolyl)furocoumarins. The advantages of transition metal catalyzed reactions to the transformations of plant metabolites and its derivatives shown the possibility of introduction of several bioisosteric groups, and other fragments providing additional interactions and selectivity of binding with receptors and enzymes.

Furocoumarins from Peucedanum baicalense of mongolia flora and their cytotoxic activity

Plants of the genus Peucedanum attract the attention of researchers as sources of coumarins. We isolated previously from P. terebinthaceum Fischer et Turcz. of Mongolia flora the pyranocoumarin (+)-pteryxin [1]. Plants of the species Ferulopsis hystrix Bunge (P. hystrix) were characterized as sources of angular furocoumarins [2]. The species P. baicalense (Redow.) Koch is broadly distributed over Mongolia [3]. Peucedanin, imperatorin, isoimperatorin, fellopterin, deltoin, bergapten, and 8-hydroxy-5-methoxypsoralen were previously isolated from its roots [3]. We studied compounds extracted from P. baicalense collected in Baruunburen, Selenge Province, Mongolia, during budding-flowering. The concentrated EtOH extract of subterranean organs was diluted with H2O. Coumarins were extracted sequentially by hexane (1.15% yield), Et2O (0.33%), and EtOAc (2.28%). An analysis of PMR spectra of the fractions showed that the principal components of the hexane extract were diacetylene compounds, coumarins (~30%), and sterols (~12%). Extracted compounds were separated by column chromatography over silica gel. Chromatography of the hexane extract (2.4 g) isolated sequentially the diacetylene alcohol falcarinol (1) and pure linear furocoumarins isoimperatorin (2) (0.032% of raw material weight), fellopterin (3) (0.038%), and 8-(1,1-dimethylallyloxy)bergapten (4) (0.044%).

Synthesis of imperatorin analogoues and their evaluation as acetylcholinestarase and butyrylcholinesterase inhibitors

In this study we analyzed inhibitory activity of some synthesized furocoumarins towards acetyl- and butyrylcholinesterase. We used fruits of Archangelica angelica L. obtained after cultivation for medical purposes, as a source of imperatorin and other linear furocoumarins. Apart from isolated imperatorin we used commercially available xanthotoxin as a substrate for chemical transformations leading to several derivatives differing in the structure of a side chain of furocoumarin rings. Anti-cholinesterase activity was evaluated in in vitro experiments according to the modified Ellman's method using 96-well plate reader. For each of synthesized compounds IC50 value for both enzymes was established basing on concentration inhibition curves. Galantamine hydrobromide was used as a positive control in enzymatic experiments. All active compounds showed significant selectivity towards butyrylcholinesterase rather than acetylcholinesterase. The most active were 8-(3-methylbutoxy)-psoralen and 8-hexoxypsolaren with IC50 for BuChE around 16.5 and 16.4µM respectively. The results of our study may be considered as the beginning of a search for potential anti-Alzheimer's disease drugs based on the structure of natural furocoumarins.

Erratum to: Simultaneous Qualitative Analysis of Coumarins in the Rhizome of Angelica polymorpha Maxim. by LC–DAD–ESI–MS

A novel method has been developed for simultaneous qualitative analysis of coumarins in the rhizome of Angelica polymorpha Maxim. with the use of high-performance liquid chromatography (LC)–photodiode array detection (DAD)–electrospray ionization (ESI)–tandem mass spectrometry (MS). LC analysis was performed on an Agilent Eclipse XDB-C18 analytical column with a gradient solvent system of water and methanol, ultraviolet (UV) absorption detection was at 300 nm and peak UV spectrum and (+) ESI–MS data were acquired by DAD and a quadrupole mass spectrometer, respectively. Eight peaks were identified as linear furocoumarins including aviprin, isopimpinellin, bergapten, isooxypeucedanin, gosferol, imperatorin, phellopterin and isoimperatorin by comparing their retention time, UV, and MS spectra with that of the authentic standards, and the analysis of UV spectra and ESI–MS data of the standards gave the characteristics of UV absorption and ESI–MS fragmentation. On the basis of the above characteristics, the possible structures of four other linear furocoumarins were deduced in LC. The other chemical structures were proposed as three angular furocoumarins, a simple coumarin, two chromones, and a cinnamic acid by comparing their UV and MS data with that of literature reports. Accordingly, the method we established can simply and accurately identify the key chemical constituents in the rhizome of A. polymorpha.