Product name: Heraclenin
Synonym name:
Catalogue No.: BP3181
Cas No.: 2880-49-1
Formula: C₁₆H₁₄O₅
Mol Weight: 286.283
Botanical Source:
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
The product could be supplied from milligrams to grams. Inquire for bulk scale.
We provide solution to improve the water-solubility of compounds, thereby facilitating the variety of activity tests and clinic uses.

For Reference Standard and R&D, Not for Human Use Directly.

Description:

Heraclenin has anticoagulant, and anti-inflammatory activities, it also has mutagenicity in Chlamydomonas reinhardii. Heraclenin can induce apoptosis in Jurkat leukemia cells, it has a strong clastogenic effect . (+)-Heraclenin displays significant levels of antiplasmodial and moderate levels of antimicrobial activities.

References:

Mutat Res. 1986 Jan-Feb;169(1-2):51-4.    

Chromosome-damaging effects of heraclenin in human lymphocytes in vitro.    

METHODS AND RESULTS:

Heraclenin, a furocoumarin with an epoxide group in its side chain, was analyzed to see if it induced structural chromosome aberrations and sister-chromatid exchanges (SCEs) in human lymphocytes in vitro. The results were compared directly with those of imperatorin, which differs from Heraclenin only in lacking an epoxide group. An equally strong clastogenic effect was found for both Heraclenin and imperatorin: the number of metaphases with breaks was increased in both cases by approximately a factor of 6. Heraclenin produced a considerable dose-dependent increase in the SCE rate, i.e., by about 60 induced SCEs/metaphase, whereas imperatorin induced only about 4 SCEs/metaphase. 

CONCLUSIONS:

The results are discussed with respect to the occurrence of structural aberrations, which are primarily due to the basic furocoumarin structure itself, whereas the large increase in the SCE rate produced by Heraclenin is most probably significantly influenced by its epoxide group.    

Mutat Res. 1986 Jan-Feb;169(1-2):47-50.    

Mutagenicity of a furocoumarin epoxide, heraclenin, in Chlamydomonas reinhardii.   

Treatment of arg- or strd mutant cells of Chlamydomonas reinhardii with a furocoumarin epoxide, Heraclenin, plus UV-A resulted in a decrease in survival and a UV-A dose-dependent increase in induced Arg+ or Strs revertants. 

METHODS AND RESULTS:

Imperatorin, a furocoumarin with a very similar structure but lacking an epoxide group showed a very similar phototoxic and photomutagenic activity in these mutant strains. Treating the mutant cells with Heraclenin or imperatorin in the dark neither influenced survival nor mutation induction. The results are discussed with respect to the involvement of the epoxide moiety of Heraclenin in mutagenicity.    

Curr. Sci., 2011, 100(11):1706-11.    

Microbial transformation of (+)-heraclenin by Aspergillus niger and evaluation of its antiplasmodial and antimicrobial activities    

METHODS AND RESULTS:

Microbial transformation of (+)-Heraclenin (1) by Aspergillus niger was studied in growth media to assess its antiplasmodial and antimicrobial activities. It was transformed to (-)-heraclenol (2) as the sole product in a stereospecific manner. The in vitro antiplasmodial activity of compounds 1 and 2 was tested with chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Further, the in vitro antibacterial activity of 1 and 2 against three Grampositive bacteria, Bacillus subtilis, Bacillus sphaericus and Staphylococcus aureus, and three Gram-negative bacteria, Pseudomonas aeruginosa, Escherichia coli and Chromobacterium violaceum was analysed using agar-plate diffusion assay. The same method was employed for the evaluation of antifungal activity against five pathogenic strains of fungi, A. niger, Rhizopus oryzae, Aspergillus flavus, Candida albicans and Saccharomyces cerevisiae. 

CONCLUSIONS:

Both furanocoumarins 1 and 2 displayed significant levels of antiplasmodial and moderate levels of antimicrobial activities against the tested pathogenic strains. Compound 2 exhibited two-fold less potent antiplasmodial activity (IC50 = 6.0 μg/ml) than the parent compound 1 (IC50 = 2.5 μg/ml), whereas no difference was observed in the antimicrobial activity of both furanocoumarins. The oxirane ring was found to be beneficial in terms of antiplasmodial activity.    

Planta Med. 2000 Apr;66(3):279-81.    

Anti-inflammatory activity of coumarins from Decatropis bicolor on TPA ear mice model.   

METHODS AND RESULTS:

From the aerial parts of Decatropis bicolor, Heraclenin (1), seselin (2), psoralen (3), imperatorin (4), skimmianine (5), and heraclenol (6), were isolated. This is the first time that coumarin-like compounds are isolated from Decatropis genus. The anti-inflammatory properties of compounds 1-6 were examined against the ear edema in mice produced by TPA. 

CONCLUSIONS:

The results suggest that the anti-inflammatory activity of each compound depends of its individual substitution on the aromatic ring rather than the coumarin skeleton itself.    

Indian J Physiol Pharmacol. 1969 Jul;13(3):153-5.    

Anticoagulant activity of Heraclenin.    

METHODS AND RESULTS:

Anticoagulant activity of Heraclenin.    

HPLC of  Heraclenin

​

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

Introduction/Overview

Neuroinflammation is the immune response of the central nervous system to various injuries, infections, or neurodegenerative diseases. Its excessive or sustained activation is a common pathological feature of various neurological diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and neuropathic pain. Traditional anti-inflammatory drugs are often limited in the treatment of neuroinflammation due to poor blood-brain barrier penetration or significant side effects. Therefore, finding highly efficient, low toxicity, and targeted lead compounds that can regulate neuroinflammatory pathways from natural products has become an important direction for current drug development. Heraclinin, a natural furan coumarin, is gradually entering the research field due to its unique chemical structure and preliminary revealed immune regulatory activity. Early studies have shown that Duhuosu can selectively activate the T cell nuclear factor (NFAT) pathway and concentration dependently inhibit T cell receptor-mediated proliferation in human primary T cells, suggesting its potential immunosuppressive and anti-inflammatory properties. In recent years, with the in-depth exploration of its pharmacological effects, the potential of Duhuosu in regulating key targets related to neuroinflammation such as AMPK, TLR4, NLRP3 inflammasome, etc. has been continuously explored. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, mechanisms of action, medicinal properties, and application prospects of Duhuosu in neuroinflammatory related diseases, in order to provide comprehensive scientific references for the in-depth research and drug development of this natural product.

Chemical structure and physicochemical properties

Heraclenin, chemical name 9- [(2,3-dihydro-2-hydroxy-2-methyl-7H-furano [3,2-g] [1] benzopyran-7-yl) oxy] -7H-furano [3,2-g] benzopyran-7-one, CAS number 2880-49-1, molecular formula C ₁ H ₁ O ₅, molecular weight 286.2830. Its core structure is linear furan coumarin, which is formed by the fusion of coumarin parent nucleus and a furan ring. This structure is an important basis for its biological activity.

In terms of physicochemical properties, the lipid water partition coefficient (LogP) of Duhuosu is 2.8758, indicating its moderate lipophilicity, which facilitates its penetration of cell membranes and biological barriers. Its topological polar surface area (TPSA) is 65.1100 Å ², which is relatively low and further supports its excellent membrane permeation potential. However, its water solubility is poor, at around 0.0093 mg/mL, which may pose challenges in formulation development. It is particularly noteworthy that, based on its physicochemical parameters, Duhuosu has a high blood-brain barrier penetration ability, which provides a key advantage for its direct action on the central nervous system and intervention in neuroinflammation. In addition, preliminary drug screening showed that its Ames test results were negative at 1.5 times the standard concentration (usually a value>2 is considered a potential mutagenic positive, and 1.5 indicates no significant mutagenicity under the experimental conditions), and there was no significant inhibition of the human ether - à - go related gene (hERG) potassium channel, suggesting a low risk of cardiac toxicity and providing preliminary positive signals for its safety evaluation.

Plant sources and extraction methods

Duhuosu mainly comes from various plants in the Apiaceae family, Angelica and Heraclium genera. Among them, the traditional Chinese medicine Duhuo (usually referring to heavy toothed hairy Angelica sinensis) Angelica pubescens Maxim. f. biserrata Shan et Yuan's dried roots and Bai Zhi（Angelica dahurica）Waiting is its important natural source. These plants are commonly used in traditional medicine for dispelling wind, dampness, promoting rheumatism, and relieving pain. Their anti-inflammatory and analgesic effects are closely related to active ingredients such as Angelica sinensis.

Organic solvent extraction is commonly used to extract Angelica sinensis from plant materials. The typical process is as follows: after crushing the dried plant roots and stems, reflux extraction or ultrasound assisted extraction is performed using solvents such as methanol, ethanol, or ethyl acetate. The crude extract was obtained by vacuum concentration of the extraction solution. Subsequently, separation and purification techniques such as silica gel column chromatography and preparative high-performance liquid chromatography (HPLC) were used to separate and refine Duhuosu based on its polarity differences with other coumarin compounds. Modern analytical techniques such as liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) can be used for qualitative and quantitative analysis of compounds during the extraction process, ensuring the purity and yield of the target product. With the development of green extraction technology, methods such as supercritical CO ₂ extraction have also been explored for efficient and low solvent residue extraction of such coumarin components.

Pharmacological activity research

The pharmacological activity research of Duhuosu has surpassed its initially discovered immunosuppressive effect, demonstrating multiple biological activities, especially in the fields of anti-inflammatory, neuroprotective, and analgesic potential.

1. Immune regulation and anti-inflammatory activity The most classic feature of Duhuosu is its concentration dependent inhibition of the proliferation response of human primary T cells triggered by T cell receptor (TCR) activation. This inhibitory effect is not widespread cytotoxicity, but rather achieved by interfering with key signaling pathways for T cell activation, laying the foundation for its application in autoimmune and inflammatory diseases. In various cellular and animal inflammatory models, Duhuo Su has shown extensive anti-inflammatory effects, significantly inhibiting the excessive production of pro-inflammatory cytokines (such as TNF - α, IL-1 β, IL-6) and inflammatory mediators (such as nitric oxide and prostaglandin E2) induced by stimuli such as lipopolysaccharides (LPS).

2. Neuroprotection and anti neuroinflammatory activity This is the current focus of research on Duhuosu. In the LPS induced activation model of microglia (the main immune cells in the central nervous system), Doxorubicin can effectively inhibit the transformation of microglia into pro-inflammatory phenotype and reduce their neurotoxicity. In the Alzheimer's disease cell model, Doxorubicin showed the ability to alleviate neuronal damage and inflammatory response induced by β - amyloid (A β) protein. Its excellent blood-brain barrier penetration enables it to directly exert its effects in the central nervous system, combating neuroinflammation, a common driving force of various neurodegenerative diseases.

3. Analgesic activity Unlike traditional nonsteroidal anti-inflammatory drugs, the analgesic effect of Duhuosu may be related to its regulation of neuroinflammation and ion channels. Research has shown that it may intervene in the transmission of pain signals by affecting the activity of pain related channels such as transient receptor potential vanillic acid subtype 1 (TRPV1), demonstrating relief effects in neuropathic pain models.

4. Other activities There are also studies reporting that Duhuosu has certain anti-tumor, antibacterial, and antioxidant activities, but the research in these areas is relatively preliminary, and its specific mechanism and in vivo effectiveness need further confirmation.

Mechanism of action and molecular targets

Duhuosu exerts pharmacological effects, especially anti neuroinflammatory effects, involving multidimensional regulation of multiple key signaling pathways and molecular targets, forming a networked mechanism of action.

1. Core mechanism: Inhibition of NFAT signaling pathway Duhuosu was initially identified as an inhibitor of NFAT (activated T cell nuclear factor). NFAT is a core transcription factor for T cell activation, proliferation, and cytokine production. Duhuosu inhibits the transcriptional activity of NFAT by interfering with the dephosphorylation and nuclear translocation of NFAT by calcineurin, ultimately suppressing the excessive activation of T cells and the release of inflammatory factors. This is the molecular basis of its immunosuppressive effect.

2. Regulating key pathways and targets of neuroinflammation：

   • AMPK (PRKAA1) activation Adenosine activated protein kinase (AMPK) is a core hub for cellular energy metabolism and inflammation regulation. Duhuosu has been proven to activate AMPK. The activation of AMPK can negatively regulate the nuclear factor kappa B (NF - κ B, whose key subunit is RELA) signaling pathway, inhibit the nuclear translocation of NF - κ B and the expression of downstream pro-inflammatory genes (such as TNF, NOS2, PTGS2), thereby exerting anti-inflammatory effects.
   • Inhibition of TLR4/NF - κ B and NLRP3 inflammasome pathway Toll like receptor 4 (TLR4) is an important receptor that recognizes patterns of pathogenic molecules such as LPS and initiates inflammatory responses. Duhuosu can inhibit TLR4 signaling and block the excessive activation of its downstream NF - κ B and mitogen activated protein kinase (MAPK) pathways. At the same time, research suggests that Duhuo Su may inhibit the assembly and activation of NLRP3 inflammasomes, reduce the activation of caspase-1 (CASP1), and thereby inhibit the maturation and release of IL-1 β and IL-18, which is a key link in controlling the amplification of the inflammatory cascade.
   • Affects MAPT (Tau protein) and cholinergic system In the context of Alzheimer's disease, Duhuosu may indirectly affect the excessive phosphorylation process of Tau protein (MAPT) through its anti-inflammatory and potential kinase regulatory effects. In addition, its potential regulation of the nicotinic acetylcholine receptor alpha 7 subunit (CHRNA7) in neurons may help improve cholinergic neurotransmission deficits, which are associated with neuroprotection and cognitive function improvement.
   • Regulating TRPV1 channel As a key molecule in pain perception, the overactivation of TRPV1 channel is involved in neuropathic pain. Duhuosu may act as a regulator to affect the function of TRPV1, providing a new explanation for its analgesic mechanism.

In summary, Duhuosu forms a synergistic network through a "multi-target, multi pathway" approach, from inhibiting excessive activation of peripheral immune cells, to regulating central microglial inflammatory response, and then affecting pain signal transduction, to jointly combat neuroinflammation and its related pathological processes.

Evaluation of drug properties and pharmacokinetics

Based on its physicochemical properties and preliminary biological data, a preliminary evaluation of the pharmacological properties of Duhuosu was conducted.

1. Absorption, distribution, metabolism, excretion (ADME)：

   • Absorption and distribution Moderate LogP values and low TPSA indicate that Angelica sinensis has good oral bioavailability potential and can be absorbed by the intestine through passive diffusion. The prediction of its high blood-brain barrier penetration is its greatest pharmacokinetic advantage for the treatment of central nervous system diseases, which is expected to enable the drug to reach effective therapeutic concentrations in the brain.
   • Metabolism and excretion As a furan coumarin compound, the metabolism of Angelica dahurica in vivo may mainly be catalyzed by the liver cytochrome P450 enzyme system (such as CYP3A4, CYP1A2), which undergoes hydroxylation, dealkylation and other reactions. Its furan ring structure may make its metabolic pathway somewhat complex. The final metabolites may be excreted from the body through bile or urine. At present, there is still a lack of in vivo research on its detailed metabolic profile, main metabolites, and excretion pathways, which will be the focus of future pharmacokinetic studies.

2. Challenges and optimization directions in drug development：

   • Poor water solubility Low water solubility (0.0093 mg/mL) may affect the development, in vivo solubility, and absorption rate of its formulation. This needs to be improved through pharmaceutical methods, such as preparing nanocrystals, liposomes, cyclodextrin inclusion complexes, or solid dispersions, to enhance their solubility and bioavailability.
   • Potential phototoxicity Furancoumarin compounds usually have photosensitivity and may cause skin phototoxic reactions. Although this characteristic of Duhuosu has not been studied in detail, the evaluation of its photosafety is crucial in its subsequent development.
   • Metabolic stability and drug interactions Further research is needed on its metabolic stability, the presence of active metabolites, and its potential as a CYP enzyme substrate or inhibitor to assess potential drug drug interaction risks.

3. Preliminary safety The negative results of Ames test and lack of hERG inhibitory activity provide preliminary safety support for its genetic toxicity and cardiac toxicity. However, a comprehensive preclinical safety evaluation, including acute toxicity, chronic toxicity, reproductive toxicity, etc., still needs to be systematically carried out.

Clinical application prospects and prospects

As a multi-target natural product for anti neuroinflammation, the clinical application prospects of Duhuosu mainly focus on neurological diseases, but may also be expanded to other fields related to immune inflammation.

1. Main application directions：

   • Neurodegenerative diseases Such as Alzheimer's disease and Parkinson's disease. Duhuosu is expected to delay disease progression by inhibiting neuroinflammation mediated by microglia, potentially intervening in A β and Tau pathology, and activating neuroprotective pathways such as AMPK. It can be used as a candidate molecule for adjuvant therapy or disease modification therapy.
   • Autoimmune central nervous system diseases Like multiple sclerosis. Its core mechanism of inhibiting T cell activation and NFAT pathway directly targets the autoimmune attack core of multiple sclerosis, and has potential therapeutic value.
   • Neuropathic Pain By regulating neuroinflammation (such as inhibiting spinal microglial activation) and pain related ion channels such as TRPV1, Duhuosu may be developed as a novel analgesic, particularly suitable for chronic pain that is insensitive to traditional analgesics or has significant side effects.
   • Other inflammatory diseases The immunosuppressive and anti-inflammatory properties of diseases such as rheumatoid arthritis and inflammatory bowel disease are also worth exploring.

2. Future research prospects and challenges：

   • In depth mechanism research It is necessary to validate its mechanism of action in disease models closer to the human body, such as humanized mouse models and organoids, and use chemical biology methods (such as probe labeling and proteomics) to identify its direct target of action.
   • Systematic pharmacokinetics and toxicology research Standardized preclinical ADME and GLP toxicology studies must be completed to clarify their treatment window, especially to evaluate their long-term safety and phototoxicity risks.
   • Structural optimization and derivative development To address its shortcomings such as poor water solubility and potential metabolic instability, a series of derivatives can be synthesized through medicinal chemical means for structural modification, in order to improve its drug properties while maintaining or enhancing its activity.
   • Combination therapy strategy Exploring the combined use of Duhuosu and existing standard therapeutic drugs (such as acetylcholinesterase inhibitors, levodopa, immunosuppressants, etc.) may result in synergistic effects, reducing their respective dosages and side effects.
   • clinical translation On the basis of sufficient preclinical research, promoting its entry into clinical trials is the ultimate way to verify its clinical efficacy and safety.

Conclusion

Duhuosu, as a natural furan coumarin isolated from traditional medicinal plants, has shown remarkable potential in the field of anti neuroinflammation and related disease treatment due to its unique chemical structure and multi-target pharmacological mechanism. From the initial discovery of its specific inhibition of the T cell NFAT pathway to the current revelation of its regulatory role in multiple neuroinflammatory key nodes such as AMPK, TLR4/NF - κ B, NLRP3 inflammasome, the breadth and depth of its research continue to expand. Its excellent blood-brain barrier penetration ability and preliminary positive pharmacological parameters provide favorable conditions for its intervention in central nervous system diseases. However, its poor water solubility, potential phototoxicity, and incomplete pharmacokinetic and toxicological data are challenges that must be overcome to move towards clinical translation. Future research needs to continue efforts in deepening the mechanism of action, systematically evaluating drug properties, conducting rational structural optimization, and exploring clinical combination therapy strategies. The research example of Duhuosu fully demonstrates the feasibility and value of exploring modern drug lead compounds from the treasure trove of traditional Chinese medicine, and is expected to provide new candidate molecules and strategies for the treatment of neuroinflammatory diseases.