Synonym name: Calycanthogenol; Phytodolor
Catalogue No.: BP0783
Cas No.: 486-21-5
Formula: C₁₁H₁₀O₅
Mol Weight: 222.196
Botanical Source: Artemisia scotina, Azadirachta indica, Fraxinus excelsior and Pterocaulon redolens

Purity: 95%~99%
Analysis Method: HPLC-DAD or/and HPLC-ELSD
Identification Method: Mass, NMR
Packing: Brown vial or HDPE plastic bottle
Can be supplied from milligrams to grams.

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

Description:

Isofraxidin has definite anti-bacterial, anti-oxidant, analgesic,and anti-inflammatory activities, it inhibits expression of MMP-7 and in vitro cell invasion at a non-toxic level through inhibiting ERK1/2 phosphorylation in hepatoma cell lines.Isofraxidin is one possible radio-protector, it can protect leukemia cells from radiation-induced apoptosis via ROS/mitochondria pathway in a p53-independent manner.

References:

Biol Pharm Bull. 2010;33(10):1716-22.    

Isofraxidin, a coumarin component from Acanthopanax senticosus, inhibits matrix metalloproteinase-7 expression and cell invasion of human hepatoma cells.   

7-Hydroxy-6,8-dimethoxy-2H-1-benzopyran-2-one (Isofraxidin) is a major coumarin component isolated from the stem bark of Acanthopanax senticosus, a widely used Chinese medicinal herb. 

METHODS AND RESULTS:

We investigated Isofraxidin in its anti-tumor effects on human hepatoma cell lines HuH-7 and HepG2. Isofraxidin significantly inhibited hepatoma cell invasion, without affecting cell attachment or growth. Expression of 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced matrix metalloproteinase-7 (MMP-7) in hepatoma cells was inhibited by Isofraxidin at the both mRNA and protein levels. This inhibition tended to be greater in cells inoculated at low density than in those at high density. Isofraxidin showed an inhibitory effect on the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) in hepatoma cells, whereas activator protein-1 (AP-1) DNA binding activity, nuclear factor-kappa B (NF-κB) nuclear translocation, and inhibitory kappa B (IκB) degradation were affected very little. 

CONCLUSIONS:

These results indicate that Isofraxidin inhibits expression of MMP-7 and in vitro cell invasion at a non-toxic level through inhibiting ERK1/2 phosphorylation in hepatoma cell lines, which suggest Isofraxidin might become an effective agent for suppressing hepatoma cell invasion.    

Immunobiology. 2015 Mar;220(3):406-13.    

Isofraxidin protects mice from LPS challenge by inhibiting pro-inflammatory cytokines and alleviating histopathological changes.    

Isofraxidin (IF), the major bioactive component of Sarcandra glabra, has been reported to be an effective anti-inflammatory compound. 

METHODS AND RESULTS:

In a previous study, we showed that Isofraxidin acts via the MAPK pathway to produce anti-inflammatory effects, both in vivo and in vitro. However, the effect and mechanism of action of Isofraxidin on inflammatory cytokines and NF-κB activation in vivo has not been investigated. We therefore aimed to evaluate how Isofraxidin regulates the production of inflammatory cytokines in vivo by intraperitoneal injection of Isofraxidin (1, 5 or 15mg/kg) prior to treatment with LPS (1mg/kg, i.p.). Macroscopic, biochemical and histopathological parameters were measured. Treatment with Isofraxidin prior to LPS challenge decreased mortality rate, body weight loss, organ coefficient and histopathological changes. Isofraxidin also suppressed the protein expression of NF-κB, levels of NO and IL-6 in serum and production of TNF-α in liver. 

CONCLUSIONS:

Our results show that pretreatment with IF increases the survival rate following LPS stimulation in mice. The effect involves regulation of NF-κB signal which, in turn, regulates production of inflammatory cytokine TNF-α, suggesting that Isofraxidin may have a therapeutic effect against LPS-induced inflammatory disease.    

Int Immunopharmacol. 2012 Oct;14(2):164-71.    

Isofraxidin exhibited anti-inflammatory effects in vivo and inhibited TNF-α production in LPS-induced mouse peritoneal macrophages in vitro via the MAPK pathway. 

Isofraxidin (IF) is a Coumarin compound that can be isolated from medicinal plants, such as Sarcandra glabra (Thunb.). Nakai is widely used in Asian countries for the treatment of anti-bacterial, anti-inflammatory and anti-tumour action. 

METHODS AND RESULTS:

The present investigation was designed to evaluate the effect of Isofraxidin on inflammation and nociception. In addition, we investigated a potential novel mechanism to explain the anti-inflammatory properties of Isofraxidin. In vivo, xylene-induced mouse ear edema, carrageenan-induced rat paw edema, LPS-induced mouse endotoxic shock, acetic acid-induced mice writhing and formalin-induced mouse pain models were used to evaluate the anti-inflammatory activity of Isofraxidin. In vitro, we examined the effects of Isofraxidin inhibition on TNF-α production and the regulation of ERK1/2 and p38 phosphorylation activity in LPS-induced mouse peritoneal macrophages. Our results demonstrated that Isofraxidin can significantly decrease xylene-induced ear edema, carrageenan-induced paw edema, acetic acid-induced writhing and formalin-induced pain. Moreover, Isofraxidin greatly inhibited the production of TNF-α in the serum of LPS-stimulated mice and peritoneal macrophages, and it decreased phospho-p38 and ERK1/2 protein expression in LPS-stimulated mouse peritoneal macrophages. 

CONCLUSIONS:

Overall, our data suggest that Isofraxidin possesses significant analgesic and anti-inflammatory activities that may be mediated through the regulation of pro-inflammatory cytokines, TNF-α and the phosphorylation of p38 and ERK1/2.    

HPLC of Isofraxidin

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

Introduction/Overview

Isofraxidin (CAS No.: 486-21-5) is a natural coumarin, mainly found in Acanthopanax senticosus, a plant in the Araliaceae family. As an important component in traditional Chinese medicine, isozine-piridine has attracted widespread attention due to its diverse bioactivity, especially showing significant potential in anti-tumor, anti-inflammatory, and neuroprotective fields. In recent years, with the advancement of molecular mechanism research on tumors, the pharmacological effects of isozine-deridine in malignant digestive tumors such as liver cancer and colon cancer have gradually been revealed. In particular, its inhibition of tumor cell invasion and the regulatory mechanisms of related signaling pathways have attracted significant academic interest.

This paper aims to systematically review the chemical structure and physicochemical properties of isozine-predine, plant origin and extraction process, pharmacological activity and mechanism of action, druggability evaluation, and pharmacokinetic characteristics. Combined with its potential applications in liver and colon cancer, it comprehensively evaluates its clinical feasibility and future research directions, providing theoretical support and practical guidance for natural product pharmacology and new drug development.

Chemical structure and physicochemical properties

Isozineperidine belongs to the coumarin-class compounds, with a molecular formula of C12H10O5 and a molecular weight of 222.1960. Its structural core is the coumarin backbone, specifically 7-hydroxy-6,8-dimethoxycoumarin. The molecule contains two methoxy groups and one hydroxyl group, giving it certain polarity and hydrophilicity. Physicochemical property data show that the LogP value of isozine-predine is 1.5384, indicating moderate lipid solubility that facilitates cell membrane penetration. The topological pole surface area (TPSA) is 68.9 Ų, indicating a good balance between membrane permeability and receptor binding.

Water solubility is 0.2775 mg/mL, making it a low-solubility compound, which limits its bioavailability to some extent, but it is expected to improve through formulation optimization. Isazine has a high blood-brain barrier penetration ability, suggesting its potential application in central nervous system diseases. The hERG channel inhibition test was negative, indicating a low risk of cardiotoxicity. The Ames mutagenicity test scored 0.9, essentially eliminating the genotoxicity risk.

Plant Origins and Extraction Methods

Isozine is mainly isolated from Acanthopanax senticosus. Eleutherococcus senticosus belongs to the Araliaceae family, genus Eleutherococcus, widely distributed in Northeast China and the Russian Far East. Traditionally, it has been used as a qi-tonifying and strengthening the body, anti-fatigue, and anti-inflammatory medicine. As one of its main active ingredients, isozine-predine is not as abundant as eleutherococcus polysaccharides and ginsenosides, but its unique biological activity makes it a research hotspot.

Common methods for extracting isozine-deridine include traditional alcohol extraction and modern ultrasound-assisted extraction and microwave-assisted extraction. Generally, 70% ethanol is used as the solvent, extracted at an appropriate temperature, followed by purification by liquid-liquid separation, column chromatography, and other methods. High-performance liquid chromatography (HPLC) and mass spectrometry techniques are widely used for qualitative and quantitative analysis of isozine-deridine to ensure the quality and batch stability of extracts.

In recent years, green extraction technologies such as supercritical CO2 extraction and membrane separation have also been attempted to be applied to the extraction of isozine-deridine, aiming to improve extraction efficiency, reduce solvent residues and environmental pollution, and promote its industrial-scale production.

Pharmacological activity research

Antitumor activity

The antitumor effects of isozineperidine in liver cancer cells have been confirmed by multiple in vitro and in vivo studies. Its main manifestation is inhibiting the proliferation, migration, and invasion ability of liver cancer cells. Studies have shown that isozine-pedicin can significantly downregulate the expression of matrix metalloproteinase-7 (MMP-7). As a key matrix-degrading enzyme in the tumor microenvironment, MMP-7 promotes tumor cell invasion and metastasis. Isazine-deridine effectively reduces the aggressiveness of liver cancer cells by inhibiting MMP-7.

In addition, isozine-deridine also regulates signaling pathways in liver cancer cells, particularly by inhibiting the phosphorylation level of ERK1/2 and blocking activation of the MAPK signaling pathway, thereby suppressing tumor cell proliferation and survival.

Anti-inflammatory and immunomodulatory effects

Isazine also exhibits significant anti-inflammatory activity. It can weaken the expression of induced nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), reduce the production of inflammatory mediators, and alleviate inflammatory responses. Isozine-deridine blocks the downstream NF-κB signaling pathway by inhibiting the formation of the Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) complex, reducing the release of pro-inflammatory cytokines and exerting immunoregulatory effects.

Other pharmacological activities

In addition to its antitumor and anti-inflammatory effects, isozine-deridine has also been reported to possess multiple biological activities including antioxidant, neuroprotective, and cardiovascular protection. For example, it reduces oxidative stress damage by scavenging free radicals and regulating intracellular antioxidant enzyme systems; In the neuron model, isozine-deridine can inhibit neuroinflammation and protect neuronal survival.

Mechanism of action and molecular targets

The pharmacological effects of isozine-deridine are mainly realized through multiple signaling pathways and molecular targets:

1. MMP-7 inhibition: MMP-7 plays a key role in the degradation and invasion of tumor cell stromal cells. Isazine-deridine reduces the degradation of the extracellular matrix by downregulating MMP-7 expression, thereby inhibiting tumor cell migration and metastasis.

2. ERK1/2 phosphorylation inhibition: ERK1/2, as an important member of the MAPK signaling pathway, regulates cell proliferation and survival. Isazine-dertimidine inhibits ERK1/2 activation, blocking signal transduction and leading to tumor cell cycle arrest and apoptosis.

3. Downregulation of iNOS and COX-2 expression: iNOS and COX-2 are key enzymes in the inflammatory response and participate in the synthesis of pro-inflammatory mediators. Isazine-deridine reduces inflammatory responses by inhibiting its expression, blocking the tumor-promoting effects related to chronic inflammation.

4. TLR4/MD-2 Complex Blockade: The TLR4/MD-2 complex is a promoter of inflammatory signaling and activates the NF-κB pathway. Isazine-deridine blocks the formation of this complex, suppresses downstream inflammatory signals, and exerts immunomodulatory and anti-inflammatory effects.

5. Potential role of colon cancer-related targets: Although isazine dermatine is mainly studied in liver cancer, its physicochemical properties and signaling pathway regulation suggest it has potential regulatory effects on colon cancer-related targets such as AMPK, BCL2, STAT3, ABCB1, ALOX5, LCK, TOP1, RELA, MAPK1, and TNF. Future research is expected to reveal its value in colon cancer treatment.

Druggability evaluation and pharmacokinetics

Druggability evaluation of isozine-dericine indicates good drug development potential. A molecular weight of 222.1960 conforms to the Lipinski rule, and a LogP value of 1.5384 indicates moderate lipid solubility, which is beneficial for oral absorption. TPSA was 68.9 Ų, indicating good cell membrane penetration capability. Although water solubility is relatively low (0.2775 mg/mL), it can be improved through formulation technology.

The high penetration of the blood-brain barrier supports its potential application in central nervous system diseases. The hERG channel inhibition test was negative, reducing the risk of cardiotoxicity. Ames trial results basically ruled out genotoxicity and showed good safety.

In terms of pharmacokinetics, isozine-deridine exhibits good oral bioavailability in animal models, with a moderate plasma half-life and effective therapeutic concentration. Its metabolism mainly occurs through the liver phase I and phase II enzyme systems, and the safety of these metabolites still requires further research. In vivo distribution shows that isozine-predine can be widely distributed in liver, kidney, and brain tissues, matching its multi-target effect.

Prospects and outlooks for clinical applications

As a natural product with multiple biological activities, isozine-dermatine shows broad clinical application prospects. In liver cancer cells, it significantly inhibits tumor invasion by inhibiting the MMP-7 and ERK1/2 signaling pathways, providing new ideas for adjuvant therapy for liver cancer. Combined with its anti-inflammatory and immunomodulatory effects, isozinpemidine is expected to be used for tumor microenvironment regulation to enhance tumor treatment outcomes.

Additionally, the potential regulatory effect of isazine-desidine on colorectal cancer-related signaling pathways suggests its potential application in colon cancer treatment. In the future, molecular mechanism research on its target should be strengthened, combined with modern drug design technologies to optimize its structure to enhance activity and selectivity.

In formulation development, to address its low water solubility, new drug delivery systems such as nanocarriers and solid dispersions can be adopted to enhance bioavailability and targeting. Safety evaluation and preclinical toxicology studies also need further improvement to lay the foundation for clinical trials.

With the deepening of precision medicine and natural drug research, isozine-piridine is expected to become an important candidate for the development of natural anti-tumor drugs, driving the modernization and internationalization of traditional Chinese medicine.

Conclusion

As an important coumarin, isozine piridine in eleutherococcus, with its unique chemical structure and excellent physicochemical properties, demonstrates multi-target and multi-pathway pharmacological activity, especially showing significant therapeutic potential in liver cancer and inflammation-related diseases. By inhibiting MMP-7 expression, blocking ERK1/2 phosphorylation, and regulating the TLR4/MD-2 complex, it reveals a complex mechanism of action and provides valuable theoretical support for the development of natural antitumor drugs.

Future research should focus on deeply analyzing its molecular target network, optimizing drug structures and formulation technologies, conducting systematic pharmacokinetic and toxicological studies, and promoting the clinical translation of isozine-deridine. Through multidisciplinary integration, isozine-deridine is expected to become a star molecule in the field of natural product pharmacology, contributing new strategies and drug options for the treatment of tumors and related diseases.