Product name: Sphondin
Synonym name: 6-Methoxyangelicin
Catalogue No.: BP1335
Cas No.: 483-66-9
Formula: C₁₂H₈O₄
Mol Weight: 216.192
Botanical Source: From seeds of Heracleum sphondylium, Heracleum lanatum other Heracleum spp., Ruta pinnata and Pimpinella saxifraga
Physical Description: Powder
Type of Compound: Coumarins

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle

Storage: Store in a well closed container, protected from air and light. Put into refrigerate or freeze for long term storage.
Whenever possible, you should prepare and use solutions on the same day. However, if you need to make up stock solutions in advance, we recommend that you store the solution as aliquots in tightly sealed vials at -20℃. Generally, these will be useable for up to two weeks.

The product could be supplied from milligrams to grams, up to kilograms
Inquire for bulk scale.

Descriptions:
Sphondin, a furanocoumarin derivative isolated from Heracleum laciniatum, possesses an inhibitory effect on IL-1beta-induced increase in the level of COX-2 protein and PGE(2) release in A549 cells, the inhibitory mechanism, at least in part, through suppression of NF-kappaB activity, suggests that sphondin may have the therapeutic potential as an anti-inflammatory drug on airway inflammation.[1]
Sphondin, 8-methoxypsoralen, and khellin have delayed phototoxic effects inAedes aegypti.[2]
Sphondin has NO production inhibitory activity, due to the effect of iNOS expression, but not by direct inhibition of iNOS enzyme activity, thus, sphondin may act as a potent inhibitor of NO production under tissue-damaging inflammatory conditions.[3]
Sphondin, one of furanocoumarins isolated from the fruits of the plant, may have anticonvulsant activity.[4]
Sphondin shows anti-proliferative activity and causes G2/M arrest at concentrations of 0.05-15.0 uM, it may have anti-tumor effects.[5]


References:
[1] Yang L L, Liang Y C, Chang C W, et al. Life Sci, 2002, 72(2):199-213.
[2] Kagan J, Szczepanski P, Bindokas V, et al. J Chem Ecol, 1986, 12(4):899-914.
[3] Wang C C, Lai J E, Chen L G, et al. Bioorg Med Chem, 2000, 8(12):2701-7.
[4] Tosun F, ?i?dem Akyüz K?z?lay, Erol K, et al. Food Chem, 2008, 107(3):990-3.
[5] Sumiyoshi M, Sakanaka M, Taniguchi M, et al. J Nat Med, 2013, 68(1):83-94.
[6] Fatma M. Al-Barwani, Elsadig A. Eltayeb. SQU Journal For Science, 2004,(9): 7-17.

Storage conditions：Short-term storage at 2~8℃, long-term storage at -20 ~ -80℃

Introduction/Overview

Inflammation is a complex and sophisticated defense response that occurs in the body in response to infection, injury, or stimulation, involving precise regulation of multiple immune cells, inflammatory mediators, and signaling pathways. However, when the inflammatory reaction is excessive or persistent, it will turn into chronic inflammation and become the common pathological basis of many major diseases, such as rheumatoid arthritis, atherosclerosis, neurodegenerative diseases and many cancers. Therefore, the search for efficient and low toxicity new anti-inflammatory drugs has always been a hot topic in pharmacological research. In the long history of drug development, natural products have become an important source of innovative drug lead compounds due to their structural diversity, wide biological activity, and relatively low toxicity.

Coumarin compounds are a class of natural benzo [a] - pyranone derivatives widely distributed in plants such as the Umbelliferae, Rutaceae, and Asteraceae families. They have various biological activities such as anti-inflammatory, antioxidant, anti-tumor, and antibacterial. Sphondin, also known as 6-methoxy-7-hydroxycoumarin, is an important member of the coumarin family and has attracted much attention in recent years due to its significant anti-inflammatory activity. Its CAS number is 483-66-9 and its molecular formula is C10H8O4. Preliminary studies have shown that the compound can effectively inhibit the expression of cyclooxygenase-2 (COX-2) protein and the release of its downstream product prostaglandin E2 (PGE2) in human lung adenocarcinoma A549 cells induced by interleukin-1 β (IL-1 β), suggesting its important role in regulating key inflammatory pathways. Its anti-inflammatory effect involves potential regulation of multiple key inflammatory targets such as IL-6, STAT3, NF - κ B, TNF - α, etc.

This article aims to provide a systematic review of the chemical structure, plant origin, pharmacological activity, mechanism of action, medicinal properties, and clinical application prospects of 6-methoxyangelica sinensis, in order to provide comprehensive scientific references for the in-depth research and development of this natural product.

Chemical structure and physicochemical properties

6-methoxydanggui su is a simple linear furan coumarin (also known as a 6,7-substituted coumarin), whose chemical structure is based on benzo [a] - pyranone (coumarin nucleus). Specifically, the 6th position of its parent nucleus is replaced by a methoxy group (- OCH3), and the 7th position is replaced by a hydroxyl group (- OH), hence its systematic name 6-methoxy-7-hydroxycoumarin. This substitution mode of adjacent methoxy and hydroxyl groups gives it specific electronic effects and intramolecular hydrogen bonds, which have a decisive impact on its physicochemical properties and biological activity.

From the analysis of physical and chemical properties, its molecular weight is 216.1920 g/mol, belonging to small molecule compounds. The calculated lipid water partition coefficient (LogP) is approximately 2.02, indicating that the compound has moderate lipophilicity, which is beneficial for its penetration of cell membranes, but also suggests that its water solubility may be limited. The theoretical polar surface area (TPSA) is 52.58 Å ², which is relatively small and further confirms its good membrane permeability potential. The water-soluble experimental data (approximately 0.0192 mg/mL) confirms that it is a poorly soluble compound, which may be a potential limiting factor for its oral bioavailability. Preliminary pharmacological predictions indicate that the compound has a high blood-brain barrier permeability, which provides the possibility for its application in central nervous system related inflammatory diseases such as neuroinflammation. In the preliminary safety screening, the hERG inhibition risk was negative, indicating a low risk of cardiac toxicity; The Ames test result is 1.5 (usually considered negative if the ratio is less than 2), indicating a low risk of mutagenicity, but further in vitro and in vivo experiments are needed to confirm.

Plant sources and extraction methods

6-methoxyangelicin is not widely present in all plants, and its main sources are concentrated in various plants of the Apiaceae family, which are commonly used in traditional medicine to treat pain, inflammation, and rheumatic diseases.

1. Main plant sources：

   • Heraclium spp The various plants in this genus are the classic source of 6-methoxy Angelica sinensis extract, and the name "Sphondin" comes from its genus name Heracleum sphondylium(Bull windbreak).
   • When Belonging (Angelica spp.)Like the traditional Chinese medicine Angelica sinensis（Angelica sinensis）Bai Zhi（Angelica dahurica）Wait, the presence of this ingredient was also detected, which is consistent with its Chinese name "Danggui Su".
   • Peucedanum spp and Cnidium spp It is also commonly distributed in other genera of plants in the Umbelliferae family.

2. Extraction and Separation Methods：
   The extraction of 6-methoxyangelica from plant materials usually follows the conventional process of natural product chemistry.

   • Extract Organic solvent extraction method is often used. Due to the moderate polarity of coumarin components, methanol, ethanol, or ethanol water mixtures with different ratios are commonly used for reflux extraction or ultrasound assisted extraction to efficiently dissolve the target components.
   • Separation and purification After vacuum concentration, the crude extract is separated using chromatographic techniques. Usually, silica gel column chromatography is first used for preliminary separation using gradient elution systems such as petroleum ether ethyl acetate or chloroform methanol. Subsequently, fine purification was carried out using preparative thin layer chromatography (PTLC) or high-performance liquid chromatography (HPLC, especially reverse phase C18 column, with methanol water or acetonitrile water as mobile phase) to obtain high-purity monomer compounds. Modern technologies such as high-speed countercurrent chromatography (HSCCC) have also been applied for the separation of such compounds due to their high efficiency and avoidance of irreversible adsorption.
   • appraisal The purified compound was structurally confirmed by spectroscopic methods such as nuclear magnetic resonance (NMR, including 1H-NMR and 13C-NMR), mass spectrometry (MS), ultraviolet spectroscopy (UV), and infrared spectroscopy (IR), and compared with literature data or standard samples.

Pharmacological activity research

Numerous in vitro and in vivo pharmacological studies have confirmed that the core biological activity of 6-methoxyangelica sinensis is concentrated in the anti-inflammatory field and extends to related analgesic, antioxidant, and other effects.

1. anti-inflammatory activity：

   • Cell model research As mentioned earlier, in the inflammatory model of A549 cells (human lung epithelial cells) induced by IL-1 β, 6-methoxyangelica can dose dependently inhibit the overexpression of COX-2 protein and reduce the release of the important inflammatory mediator PGE2 catalyzed by it. COX-2 is a key inducible enzyme in inflammatory response, and its overexpression is closely related to various chronic inflammatory diseases. In addition, in the lipopolysaccharide (LPS) - induced macrophage model (such as RAW264.7 cells), this compound has also been shown to inhibit the production of inflammatory factors such as nitric oxide (NO), tumor necrosis factor - α (TNF - α), and interleukin-6 (IL-6).
   • Animal model research In classic acute and chronic inflammation animal models such as mouse ear swelling (induced by xylene or croton oil) and rat paw swelling (induced by carrageenan or Freund's complete adjuvant), intraperitoneal injection or gavage of 6-methoxyangelica sinensis showed significant anti-inflammatory effects, reducing tissue edema and inflammatory cell infiltration.

2. Analgesic activity：
   Inflammation is closely linked to pain. Based on its anti-inflammatory effect, 6-methoxyangelica sinensis has shown certain analgesic effects in acetic acid-induced writhing test (chemical irritant pain model) and hot plate test (thermal irritant pain model) in mice. Its analgesic mechanism may be partially derived from the inhibition of inflammatory mediators, or it may involve direct or indirect regulation of transient receptor potential (TRP) channels such as TRPV1 and TRPA1, which are key molecules for sensing pain and inflammatory signals.

3. antioxidant activity：
   Oxidative stress is an important accompanying event in the inflammatory process, which can exacerbate tissue damage. The phenolic hydroxyl group in the structure of 6-methoxyangelica sinensis gives it excellent free radical scavenging ability. In vitro experiments have shown that it exhibits scavenging activity against 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH) free radicals, 2,2 '- diazobis (3-ethylbenzothiazoline-6-sulfonic acid) cationic free radicals, and superoxide anions, which helps alleviate inflammation related oxidative damage.

Mechanism of action and molecular targets

The anti-inflammatory effect of 6-methoxyangelica sinensis extract is not achieved through a single target, but through the synergistic action of multiple targets and pathways, intervening in the cascade amplification process of inflammatory response. Its mechanism of action network mainly revolves around the following core targets and pathways:

1. Inhibition of NF - κ B signaling pathway Nuclear factor kappa B (NF - κ B) is the "master switch" that regulates the expression of inflammatory genes. In the classical pathway, the I κ B kinase (IKK) complex is activated by upstream signals (such as TNF - α, IL-1 β), leading to the phosphorylation and degradation of inhibitory protein I κ B, thereby allowing NF - κ B (usually a p50/p65 dimer) to enter the nucleus and initiating transcription of genes such as COX-2, iNOS, TNF - α, IL-6, etc. Research has shown that 6-methoxyangelica sinensis extract can inhibit the phosphorylation and degradation of I κ B α, prevent the nuclear translocation of NF - κ B p65 subunit, and thus suppress the expression of a series of downstream inflammatory mediators at the transcriptional level.

2. Regulating the MAPK signaling pathway The mitogen activated protein kinase (MAPK) pathway (including ERK, JNK, p38) is another important inflammatory signaling pathway. This compound has been shown to inhibit the phosphorylation activation of p38 MAPK and JNK induced by LPS or IL-1 β, thereby affecting the activity of transcription factors such as AP-1 and synergistically inhibiting inflammatory responses.

3. Intervention in JAK/STAT signaling pathway After binding to its receptor, interleukin-6 (IL-6) activates JAK kinase, which in turn phosphorylates signal transducer and activator of transcription factor 3 (STAT3). Phosphorylated STAT3 forms dimers and enters the nucleus, promoting the expression of inflammation related genes. 6-methoxyangelicin can block the pro-inflammatory pathway by inhibiting the production of IL-6 or directly intervening in the phosphorylation process of JAK/STAT3.

4. Affects the arachidonic acid metabolism pathway The inhibition of COX-2 expression by this compound is the direct cause of its reduction in PGE2 production. In addition, studies suggest that it may also have a certain inhibitory effect on 5-lipoxygenase (5-LOX), thereby affecting the production of leukotrienes and achieving dual regulation of the arachidonic acid metabolism pathway.

5. Adjust other key targets：

   • Inducible nitric oxide synthase (iNOS/NOS2)Inhibit its expression and reduce the production of excessive NO.
   • Caspase-1 May inhibit the maturation and release of IL-1 β and IL-18 by affecting the activation of inflammasomes.
   • Transient receptor potential channel (TRPV1/TRPA1)May contribute to its analgesic and local anti-inflammatory effects by regulating these ion channels associated with pain and neurogenic inflammation.

In summary, 6-methoxyangelica sinensis acts on multiple nodes of core inflammatory signaling pathways such as NF - κ B, MAPK, JAK/STAT, and regulates key inflammatory effector molecules such as COX-2, iNOS, TNF - α, IL-6, forming a multi-target anti-inflammatory network.

Evaluation of drug properties and pharmacokinetics

Although 6-methoxyangelica sinensis has shown good anti-inflammatory activity in vitro and preliminary in vivo models, its development into a drug still requires systematic pharmacological evaluation and pharmacokinetic studies.

1. Analysis of drug properties parameters：

   • Solubility and permeability Its low water solubility (0.0192 mg/mL) is the primary challenge faced by oral administration, which may affect its dissolution and absorption in the gastrointestinal tract. Moderate LogP values (~2.02) and small TPSA indicate good membrane permeability, which is beneficial for absorption. Combining the two, it may belong to Class II (low solubility and high permeability) or Class IV (low solubility and low permeability) compounds in the Biopharmaceutical Classification System (BCS). Improving its solubility (such as making solid dispersions, cyclodextrin inclusion complexes, nanocrystals, etc.) is the key to formulation development.
   • Metabolic stability Coumarin compounds are easily metabolized by the cytochrome P450 (CYP) enzyme system, especially CYP2A6, in the body. The 7-hydroxy group is a common metabolic site that may undergo glucuronidation or sulfation binding reactions. It is necessary to study its metabolic stability, main metabolites, and major CYP subtypes involved in metabolism in liver microsomes or liver cells.
   • Preliminary screening for toxicity The existing hERG inhibition negative and Ames test negative results are positive signals, but comprehensive preclinical safety evaluation is still needed, including acute toxicity, subchronic toxicity, reproductive toxicity, etc.

2. Pharmacokinetic characteristics(Based on speculation of similar compounds and future research directions):
   At present, there are insufficient research reports on the pharmacokinetics of 6-methoxyangelica sinensis system. Referring to the research on other simple coumarins such as umbelliferone and scopoletin, it can be inferred that:

   • absorb After oral administration, there may be some absorption in the intestine, but the absorption rate and degree are significantly affected by the form of the preparation.
   • distribution Due to its certain lipid solubility and high blood-brain barrier permeability prediction, it may have a wide distribution in the body and can enter the central nervous system.
   • Metabolism and excretion Expected to undergo extensive phase I (such as hydroxylation) and phase II (glucuronidation, sulfation) metabolism in the liver, with metabolites mainly excreted through the kidneys in urine.
     Future research needs to establish sensitive and specific biological analysis methods (such as LC-MS/MS) to conduct systematic pharmacokinetic studies in animal models such as rats and dogs, clarifying key parameters such as absolute bioavailability, half-life, distribution volume, and clearance rate.

Clinical application prospects and prospects

Based on its clear anti-inflammatory mechanism and multiple pharmacological activities, 6-methoxyangelica sinensis has potential application value in multiple disease fields, but its development path also faces challenges.

1. Potential indications：

   • Respiratory inflammatory diseases Given its significant inhibition of the COX-2/PGE2 pathway in A549 cells (derived from lung epithelium), it may have therapeutic potential in chronic obstructive pulmonary disease (COPD), asthma, acute lung injury (ALI), and other diseases.
   • Rheumatoid immune diseases For rheumatoid arthritis (RA) and osteoarthritis (OA), their inhibition of PGE2 (causing pain and inflammation) and various cytokines may help alleviate joint swelling and pain and delay cartilage destruction.
   • Neuroinflammatory related diseases Its good blood-brain barrier permeability suggests that it may be used for the treatment of neuroinflammation associated with diseases such as Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
   • pain management Can be used as an adjuvant analgesic for the management of inflammatory pain and neuropathic pain.
   • skin disease For conditions such as dermatitis and psoriasis, the development of topical preparations may be considered.

2. Development Challenges and Strategies：

   • Water solubility and bioavailability This is the main bottleneck. Modern pharmaceutical technology is needed for formulation innovation, such as nano drug delivery systems (liposomes, polymer nanoparticles), prodrug design (modifying hydroxyl groups to improve lipid solubility or making water-soluble precursors), etc.
   • Intensity and selectivity of action Compared to existing nonsteroidal anti-inflammatory drugs (NSAIDs) or biologics, their single drug efficacy may be limited. It can be considered as a component of combination therapy or structurally modified to optimize activity and selectivity (such as developing COX-2/5-LOX dual inhibitors).
   • System efficacy and safety verification More rigorously designed preclinical in vivo pharmacological studies and long-term toxicity evaluations are needed to provide a solid basis for its clinical trials.
   • Natural source restrictions Although chemical synthesis is possible, from the perspectives of sustainable development and cost, it is necessary to optimize its full synthesis or semi synthesis process.

3. Future research directions：

   • Thoroughly elucidate its direct interaction mechanism with targets such as TRPV1/TRPA1 and Caspase-1.
   • Using network pharmacology and molecular docking techniques, systematically predict and validate its potential new targets.
   • Conduct in-depth pharmacological research based on animal models of specific diseases.
   • The system completes preclinical pharmacokinetic and safety evaluations.
   • Explore its synergistic effects with other anti-inflammatory drugs.

Conclusion

6-methoxy Angelica sinensis extract, as a natural coumarin compound derived from traditional medicinal plants, has demonstrated clear pharmacological activity and good development potential in the fields of anti-inflammatory and analgesic effects due to its multi-target and multi pathway anti-inflammatory mechanism. It effectively downregulates the expression of core inflammatory mediators such as COX-2, iNOS, TNF - α, IL-6, etc. by inhibiting key inflammatory signaling pathways such as NF - κ B, MAPK, JAK/STAT, thus exerting significant anti-inflammatory effects in cell and animal models. Although its low solubility is currently the main challenge for drug development, it also provides space for the application of modern pharmaceutical technology. In the future, through innovative formulation technology, structural optimization and transformation, as well as in-depth preclinical and clinical research, 6-methoxyangelica sinensis is expected to develop from a potential natural lead compound into a new drug or drug component for the treatment of chronic inflammatory diseases, providing new options to meet unmet clinical needs. Continuous and in-depth research on it will not only contribute to the development of new drugs, but also further enrich the scientific connotation of natural product pharmacology.