Product name: Scopoletin
Synonym name: Chrysatropic acid; Gelseminic acid; β-Methylaesculetin; Buxuletin; Escopoletin; Scopoletol; Baogongteng B; Murrayetin
Catalogue No.: BP1275
Cas No.: 92-61-5
Formula: C₁₀H₈O₄
Mol Weight: 192.17
Botanical Source: Hedyotis Diffusae Herba
Physical Description:
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
Inquire for bulk scale.

Description:

Scopoletin exhibits antifungal, anti-allergic, anti-aging, and hypouricemic activities, it exerts anti-RA action probably through suppressing IL-6 production from fibroblast-like synoviocytes via MAPK/PKC/CREB pathways. Scopoletin can ameliorate alcohol-induced hepatic lipid accumulation by modulating AMPK-SREBP pathway-mediated lipogenesis in mice fed a high-fat diet.

References:

J Exp Bot. 2014 Aug;65(15):4305-15.    

Scopoletin is a phytoalexin against Alternaria alternata in wild tobacco dependent on jasmonate signalling.    

Alternaria alternata (tobacco pathotype) is a necrotrophic fungus causing severe losses in Nicotiana species by infection of mature leaves. Similar to what has been observed in cultivated tobacco, N. tabacum, young leaves of wild tobacco, N. attenuata, were more resistant to A. alternata than mature leaves, and this was correlated with stronger blue fluorescence induced after infection. However, the nature of the fluorescence-emitting compound, its role in defence, and its regulation were not clear. 

METHODS AND RESULTS:

Silencing feruloyl-CoA 6'-hydroxylase 1 (F6'H1), the gene encoding the key enzyme for Scopoletin biosynthesis, by virus-induced gene silencing (VIGS) revealed that the blue fluorescence was mainly emitted by Scopoletin and its β-glycoside form, scopolin. Further analysis showed that Scopoletin exhibited strong antifungal activity against A. alternata in vitro and in vivo. Importantly, jasmonic acid (JA) levels were highly elicited in young leaves but much less in mature leaves after infection; and fungus-elicited Scopoletin was absent in JA-deficient plants, but was largely restored with methyl jasmonate treatments. Consistent with this, plants strongly impaired in JA biosynthesis and perception were highly susceptible to A. alternata in the same way Scopoletin/scopolin-depleted VIGS F6'H1 plants. Furthermore, silencing MYC2, a master regulator of most JA responses, reduced A. alternata-induced NaF6'H1 transcripts and Scopoletin. 

CONCLUSIONS:

Thus, it is concluded that JA signalling is activated in N. attenuata leaves after infection, which subsequently regulates Scopoletin biosynthesis for the defence against A. alternata partly through MYC2, and higher levels of Scopoletin accumulated in young leaves account for their strong resistance.    

Phytomedicine. 2015 Mar 15;22(3):362-8.    

Scopoletin has a potential activity for anti-aging via autophagy in human lung fibroblasts.    

Autophagy was known to be associated with aging in addition to cancer and neurodegeneration. The effects of Scopoletin on autophagy and anti-aging were investigated in human lung fibroblast cell line, IMR 90. 

METHODS AND RESULTS:

Here we show that Scopoletin induces autophagy. It is also identified that the modulation of p53 by Scopoletin are related to the induction of autophagy. Moreover, the level of SA-β-Gal staining, an aging marker, is reduced by Scopoletin. In addition, while the expression levels of histone deacetylases such as HDAC1, SIRT1 and SIRT6 are increased in IMR 90 cells in the presence of Scopoletin, the expression levels of histone acetyltransferases are decreased. Furthermore, Scopoletin enhances the level of transcription factors such as Nrf-2and p-FoxO1 related to anti-aging. In addition, Scopoletin modulates the reprogramming proteins. 

CONCLUSIONS:

Therefore, these findings suggest that Scopoletin could exert a positive effect on anti-aging related to autophagy through modulation of p53 in human lung fibroblasts.    

Metabolism. 2014 Apr;63(4):593-601.    

Scopoletin prevents alcohol-induced hepatic lipid accumulation by modulating the AMPK-SREBP pathway in diet-induced obese mice.    

This study investigated the effects of Scopoletin on alcohol-induced hepatic lipid accumulation in diet-induced obese mice and its mechanism. 

METHODS AND RESULTS:

Alcohol (25% v/v, 5g/kg body weight) was orally administered once a day for 6 weeks to mice fed with a high-fat diet (35%kcal) with or without Scopoletin (0.05%, wt/wt). Scopoletin reduced plasma acetaldehyde, fatty acid, total cholesterol, triglyceride and insulin levels, hepatic lipid and droplets and fasting blood glucose levels that were increased by alcohol. Scopoletin significantly activated hepatic AMPK and inhibited ACC and SREBP-1c and the activities of lipogenic enzymes, such as FAS, PAP and G6PD compared to the alcohol control group. Moreover, Scopoletinsignificantly inhibited hepatic CYP2E1 activity and protein levels but elevated the activities of SOD, CAT, GSH-Px and GST and the levels of GSH compared to the alcohol control group. The hepatic lipid peroxide level was significantly lowered by Scopoletin supplementation in alcohol-administered obese mice. 

CONCLUSIONS:

Taken together, these results suggested that Scopoletin can ameliorate alcohol-induced hepatic lipid accumulation by modulating AMPK-SREBP pathway-mediated lipogenesis in mice fed a high-fat diet.    

J Med Chem. 2004 Dec 2;47(25):6248-54.    

Acetylcholinesterase inhibitory activity of scopolin and scopoletin discovered by virtual screening of natural products.

METHODS AND RESULTS:

Scopoletin exhibited an immediate and dose-dependent hypouricemic effect after intraperitoneal administration (50, 100, 200 mg/kg) in hyperuricemic mice induced by potassium oxonate; however, it did not affect the serum uric acid level in normal mice at the tested doses. For exploring the involved mechanisms of action of Scopoletin, potential inhibitory effects on xanthine oxidase and possible uricosuric effects were investigated. Scopoletin (50, 100, 200 mg/kg) significantly inhibited the activity of xanthine oxidase in liver homogenates of hyperuricemic mice although it only showed a relatively weak, albeit competitive-type, inhibition of xanthine oxidase in a commercial assay. Furthermore, a potent uricosuric effect of Scopoletin (100, 200 mg/kg) was ascertained. 

CONCLUSIONS:

These results demonstrated for the first time that Scopoletin exhibits, hypouricemic activities through decreasing uric acid production and as well as a uricosuric mechanism.    

HPLC of Scopoletin

HNMR of Scopoletin

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

Introduction/Overview

Natural products, as an important treasure trove for drug discovery and development, play an irreplaceable role in the long history of human fight against diseases. Coumarin compounds, as one of the structurally diverse and biologically active families, have always been of great concern to pharmacological researchers. Scopolatin (CAS number: 92-61-5), as a typical hydroxycoumarin derivative, is a 6-methoxy substituent of umbelliferone. It is widely distributed in various medicinal plants such as Solanaceae (such as Scopola), Asteraceae, Rutaceae, etc. Traditionally, these plants are often used for pain relief, anti-inflammatory, and antispasmodic purposes. Modern pharmacological research has revealed that scopoletin is not only an important growth regulator and secondary metabolite in plants, but also exhibits various biological activities, especially its significant anti-inflammatory and acetylcholinesterase inhibitory activities, which have become a research hotspot. Its mechanism of action involves the regulation of multiple key inflammatory targets such as interleukin-6 (IL-6), signal transduction and transcription activator 3 (STAT3), nuclear factor kappa B (NF - κ B), and cyclooxygenase (COX), indicating its broad potential for development in neurodegenerative diseases, chronic inflammatory diseases, and other fields. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, and pharmacological properties of scopoletin, and to provide prospects for its clinical application.

Chemical structure and physicochemical properties

The chemical name of scopoletin is 7-hydroxy-6-methoxy-2H-1-benzopyran-2-one, with a molecular formula of C ₁₀ H ₈ O ₄ and a molecular weight of 192.17 g/mol. Its basic skeleton is benzo [a] - pyranone, which is the coumarin nucleus. Specifically, on the benzene ring of coumarin's basic structure, the 7th position is replaced by a hydroxyl group (- OH) and the 6th position is replaced by a methoxy group (- OCH ∝). This specific substitution pattern is an important structural basis for its biological activity.

From the analysis of physical and chemical properties, scopoletin is a white or off white crystalline powder. The calculated lipid water partition coefficient (LogP) is approximately 1.58, indicating that the compound has a certain lipophilicity but is not excessively hydrophobic, which is beneficial for its penetration of cell membranes. The topologically polar surface area (TPSA) is 59.67 Å ², which is relatively small, indicating good membrane permeability. The experimental data shows that its water solubility is about 0.48 mg/mL, which is slightly soluble, which may limit its oral bioavailability to some extent. It is worth noting that based on its physicochemical parameters, scopoletin has a high blood-brain barrier permeability, which provides an important material basis for its action on central nervous system targets such as acetylcholinesterase. In addition, preliminary drug safety screening showed that its Ames test result was 0.9 (usually considered negative if less than 2), indicating a low risk of mutagenicity; At the same time, it has no significant inhibitory effect on hERG potassium channels, indicating that its potential risk of arrhythmia is relatively small, providing a favorable safety starting point for its further development.

Plant sources and extraction methods

Scopolamine lactone is widely distributed in nature and is a characteristic or important active ingredient of various medicinal plants.
Main plant sources including:
1. Solanaceae plants Like a golden flower（Datura metel）Scopola（Hyoscyamus niger）Wait, scopoletin is often named after the plant it comes from - scopolamine（Scopolia Related to spp.
2. Asteraceae plants In the Artemisia genus（Artemisia）It exists in various plants.
3. Rutaceae plants Like white fresh skin（Dictamnus dasycarpus）Wait.
4. Other sources It is also commonly found in plants of the Umbelliferae and Osmanthus families. It usually exists in the form of free glycosides or glycosides combined with sugars (such as scopolamine) in plant bodies. It is a secondary metabolite that plants produce in response to biotic and abiotic stress, and also participates in regulating plant growth.

Extraction and Separation Methods Mainly dependent on its physical and chemical properties:
1. Solvent extraction method The most commonly used preliminary extraction method. Due to the polarity and solubility of scopoletin, dry plant materials are often subjected to cold soaking, reflux, or ultrasound assisted extraction using methanol, ethanol, acetone, or their aqueous solutions. Ethanol is the most commonly used due to its safety, low cost, and high extraction efficiency.
2. Separation and purification technology After concentration, the crude extract needs further separation and purification.
* Liquid-liquid extraction Preliminary enrichment was carried out by utilizing the distribution differences of scopoletin in organic solvents (such as ethyl acetate, chloroform) and aqueous phases.
* column chromatography: is the core means of obtaining high-purity monomers. Silica gel column chromatography is commonly used for separation, using gradient elution systems such as petroleum ether ethyl acetate or chloroform methanol. In addition, reversed-phase C18 column chromatography and Sephadex LH-20 column chromatography are also widely used.
* recrystallization Purification using the temperature dependent solubility differences in specific solvents such as methanol and ethanol is a classic method for obtaining high-purity crystals.
3. Modern analytical techniques High performance liquid chromatography (HPLC), especially preparative HPLC, has become a key technology for rapid and efficient separation of scopoletin. Thin layer chromatography (TLC) and HPLC combined with ultraviolet detection (usually with maximum absorption wavelengths around 230-240 nm and 340-350 nm) are commonly used for qualitative and quantitative analysis.

Pharmacological activity research

A large number of pharmacological studies both in vitro and in vivo have confirmed that scopoletin has various biological activities, among which anti-inflammatory and neuroprotective effects are the most prominent.

1. anti-inflammatory activity This is the most extensively studied and well supported activity of scopoletin. In various animal models of acute and chronic inflammation, such as rat paw swelling induced by carrageenan or carrageenan, increased intra-abdominal capillary permeability induced by acetic acid in mice, cotton ball induced granuloma, and Freund's complete adjuvant induced arthritis model, scopoletin has shown significant inhibitory effects. It can effectively reduce the levels of inflammatory mediators such as prostaglandin E2 (PGE2) and nitric oxide (NO) at the site of inflammation, alleviate tissue edema and inflammatory cell infiltration.

2. Neuroprotection and Acetylcholinesterase Inhibition Activity Scopolamine lactone has been identified as an acetylcholinesterase (AChE) inhibitor. By inhibiting AChE and reducing the hydrolysis of acetylcholine (ACh), the level of ACh in synaptic cleft is increased. This effect synergizes with its anti-inflammatory and antioxidant activities, showing a protective effect in experimental models of neurodegenerative diseases such as Alzheimer's disease. For example, in the cognitive impairment model induced by scopolamine or A β, scopoletin can improve learning and memory abilities.

3. Analgesic and antispasmodic activity Consistent with traditional applications, scopoletin has central and peripheral analgesic effects, and its mechanism may be related to anti-inflammatory effects, regulation of ion channels (such as TRPV1, TRPA1), and central neurotransmitter system. At the same time, it can relax smooth muscles and alleviate spasms in the intestines, bronchi, and other areas.

4. antioxidant activity The phenolic hydroxyl structure of scopoletin enables it to scavenge free radicals such as DPPH and ABTS, inhibit lipid peroxidation, and exhibit antioxidant capacity. This plays an auxiliary role in reducing oxidative stress-related tissue damage.

5. Other activities The study also reported the potential activities of scopoletin in anti-tumor, antibacterial, antihypertensive, and blood glucose regulation, but the depth and systematicity of related research still need to be strengthened.

Mechanism of action and molecular targets

The multiple pharmacological effects of scopoletin stem from its multi-target regulatory ability on complex cellular signaling networks, particularly in the anti-inflammatory pathway.

1. Regulating the NF - κ B signaling pathway Nuclear factor kappa B (NF - κ B) is the core transcription factor in inflammatory response. Scopolamine can inhibit the phosphorylation and degradation of I κ B α, thereby preventing the translocation of NF - κ B p65 subunit to the nucleus. This leads to a decrease in transcription of a series of pro-inflammatory cytokine genes downstream, including TNF-α、IL-6、Inducible nitric oxide synthase (iNOS/NOS2) and Cyclooxygenase-2 (COX-2/PTGS2)Inhibition of COX-2 expression and subsequent reduction of PGE2 synthesis is one of the key steps in its anti-inflammatory effect.

2. Inhibit STAT3 activation Signal transducer and activator of transcription factor 3 (STAT3) is another important pro-inflammatory and pro survival pathway. Scopolamine can inhibit STAT3 phosphorylation (activation) induced by cytokines such as IL-6, block downstream gene expression, and synergistically enhance anti-inflammatory effects.

3. Regulating inflammasome activity Research has shown that scopoletin can inhibit the assembly and activation of NLRP3 inflammasomes, manifested as a decrease in caspase-1（CASP1） The activation level is reduced, thereby decreasing the release of mature inflammatory factors such as interleukin-1 β (IL-1 β) and IL-18.

4. Affects pain related ion channels Transient receptor potential vanillic acid subtype 1 (TRPV1) and anchored protein subtype 1 (TRPA1) are key ion channels involved in pain perception and neurogenic inflammation. Scopolamine has been shown to regulate the activity of these channels, which may be an important peripheral mechanism for its analgesic effect.

5. Directly inhibit enzyme activity：

   • Acetylcholinesterase (AChE)As a competitive or mixed inhibitor, it directly binds to the active site of AChE.
   • Cyclooxygenase (COX)In addition to inhibiting COX-2 expression, some studies suggest that it may also have an impact on COX-1（PTGS1） It has a direct inhibitory effect on COX-2 enzyme activity.
   • Nitric oxide synthase (iNOS)Inhibit its enzyme activity and expression.

In summary, scopoletin acts on NF-κB、STAT3、 Inflammasome Wait for the upstream key nodes of multiple signal axes and directly adjust them AChE, COX, TRP channels By targeting specific targets, a multi-target, networked mode of action is formed to jointly exert its comprehensive effects of anti-inflammatory, neuroprotective, and analgesic effects.

Evaluation of drug properties and pharmacokinetics

Although scopoletin has shown good activity in vitro and animal models, its drug like and pharmacokinetic properties are key factors determining its successful development as a drug.

1. Analysis of drug properties parameters According to the "Rule of Five" principle, it is preliminarily judged that scopoletin has a small molecular weight (192.17), a moderate number of hydrogen bond donors (1- OH) and acceptors (4), and an ideal LogP value (~1.58), which basically meets the general requirements of oral medication. Its high blood-brain barrier permeability prediction is its unique advantage for central nervous system diseases. The lower risk of hERG inhibition and negative Ames test results provide preliminary support for its safety assessment.

2. Pharmacokinetic study(Based on existing limited research):

   • absorb As a biopharmaceutical classification system (BCS) class II (low solubility, high permeability) or class IV (low solubility, low permeability) compound, its oral absorption may be limited by solubility and first pass effects. Research has shown that it is absorbed quickly in the intestine, but its absolute bioavailability needs to be accurately determined.
   • distribution Thanks to its moderate lipid solubility and small molecular weight, scopoletin is widely distributed in the body and can enter multiple tissues, including the brain, consistent with the predicted high BBB permeability.
   • Metabolism The main metabolic pathways of coumarin compounds include hydroxylation, demethylation, glucuronidation, and sulfation. The 7-hydroxyl and 6-methoxy groups of scopoletin are the main metabolic sites. The liver microsomal cytochrome P450 enzyme system (such as CYP450) may be involved in its metabolism. Its metabolites, such as the demethylated umbelliferone, may still be active.
   • excretion Mainly excreted through urine and bile in the form of glucuronic acid complexes or sulfate complexes.
   • challenge The main challenge may lie in the low oral bioavailability and fast metabolic rate, resulting in a short half-life, which may require optimization through structural modification or formulation methods (such as nanomaterials, phospholipid complexes, prodrug strategies).

Clinical application prospects and prospects

The multi-target pharmacological properties of scopoletin provide possibilities for its application in various disease fields.

1. Potential therapeutic areas：

   • Neurodegenerative diseases As an AChE inhibitor with both anti-inflammatory and antioxidant activities, scopoletin is a potential multi-target directed drug (MTDL) candidate molecule for the treatment of Alzheimer's disease. Its inhibitory effect on neuroinflammation also has positive implications for Parkinson's disease, amyotrophic lateral sclerosis, and other conditions.
   • Chronic inflammatory diseases Such as rheumatoid arthritis, osteoarthritis, inflammatory bowel disease, etc. It may have advantages over single target drugs by targeting multiple anti-inflammatory agents such as NF - κ B and COX-2, and may reduce the side effects of long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs).
   • pain management Especially chronic neuropathic pain and inflammatory pain, their dual mechanisms of anti-inflammatory and TRP channel regulation deserve further exploration.
   • Other There are also preliminary studies on cardiovascular diseases (anti atherosclerosis) and metabolic diseases (diabetes and its complications).

2. Development Strategy and Prospects：

   • structural optimization Using it as the parent nucleus, structural modifications are carried out to enhance activity, selectivity, and pharmacokinetic properties. For example, modifying hydroxyl and methoxy groups, or assembling other pharmacophores.
   • Innovation in formulation technology Develop novel delivery systems such as nanocrystals, liposomes, and microemulsions to improve their solubility, stability, and bioavailability, and achieve targeted delivery.
   • In depth mechanism research By utilizing techniques such as chemical biology, molecular docking, and gene knockout, we aim to more accurately elucidate the interaction patterns with key targets such as STAT3 and inflammasomes.
   • Preclinical and clinical research The system needs to complete a pre clinical safety evaluation (toxicology, pharmacokinetics) that meets the standards, and design a reasonable clinical trial plan to verify its effectiveness and safety in the human body.
   • Natural medicine development As a rich natural ingredient, it can be directly developed into standardized plant medicine or health food, used to assist in anti-inflammatory, sedative and sedative effects.

Conclusion

As a widely sourced and structurally clear natural hydroxycoumarin, scopoletin has become a star molecule in natural product pharmacology research due to its excellent anti-inflammatory activity, clear acetylcholinesterase inhibition ability, and multi-target mechanism of action. From regulating core inflammatory signaling pathways such as NF - κ B and STAT3, to directly acting on AChE, COX, and TRP ion channels, its networked pharmacological mode of action aligns with the concept of modern multi-target drug development. Although it may face challenges in drug development, especially in terms of solubility and metabolic stability, its good blood-brain barrier permeability and preliminary safety data have laid a solid foundation for its further development. In the future, through in-depth mechanism exploration, rational structural optimization, and advanced formulation technology, scopoletin is highly likely to transform from a traditional plant component into a new drug lead compound or drug for treating major health problems such as neurodegenerative diseases and chronic inflammation, fully demonstrating the sustained vitality and value of natural products in innovative drug development.