Product name: Chebulagic acid
Synonym name:
Catalogue No.: BP0338
Cas No.: 23094-71-5
Formula: C₄₁H₃₀O₂₇
Mol Weight: 954.664
Botanical Source: Tannin derived from divi-divi (fruit of Caesalpinia coriaria) and myrobalans (fruit of Terminalia chebula). Present in Geranium spp.
Physical Description: Powder
Type of Compound: Phenols

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:
Chebulagic acid, isolated from the fruits of Terminalia, it shows potent COX–LOX dual inhibition activity with IC50 values of 15 ± 0.288, 0.92 ± 0.011 and 2.1 ± 0.057 μM for COX-1, COX-2 and 5-LOX respectively, it also shows anti-proliferative activity against HCT-15, COLO-205, MDA-MB-231, DU-145 and K562 cell lines, it induces apoptosis in COLO-205 cell line.[1]
Chebulagic acid significantly suppresses the onset and progression of arthritis (CIA) in mice, immune suppression via the induction of TGFbeta and CD4+,CD25+ T cells may represent a new strategy in the development of therapies for managing rheumatoid arthritis and other inflammatory diseases.[2]
Chebulagic acid , a natural anti-oxidant, shows potent anti-inflammatory effects by suppressing NF-κB and MAPK activation in LPS-stimulated RAW 264.7, a mouse macrophage cell line. [3]
Chebulagic acid can reduce the viral cytopathic effect on rhabdomyosarcoma cells with an IC50 of 12.5 ug/mL, the utilization of the chebulagic acid treatment on mice challenged with a lethal dose of enterovirus 71 is able to efficiently reduce mortality and relieve clinical symptoms through the inhibition of viral replication, suggests that chebulagic acid may represent a potential therapeutic agent to control infections to enterovirus 71.[4]
Chebulagic acid and punicalagin have broad-spectrum antiviral activity against viruses that use glycosaminoglycans for entry.[5]
Chebulagic Acid is a potent α-glucosidase inhibitor, has anti-hyperglycemic effect .[6,7]
Chebulagic acid has neuroprotective effect via autophagy induction in SH-SY5Y cells.[8]

References:
[1] Reddy D B, Reddy T C M, Jyotsna G, et al. J Ethnopharmacol, 2009, 124(3):506-12.
[2] Sang-Ik Lee ?, Hyun P M, Kim S H, et al. Arthritis & Rheumatol, 2005, 52(1):345-53.
[3] Reddy D B, Reddanna P. Biochem Bioph Res Co, 2009, 381(1):112-7.
[4] Yang Y, Xiu J, Liu J, et al. Int J Mol Sci, 2013, 14(5):9618-27.
[5] Lin L T, Chen T Y, Lin S C, et al. Bmc Microbiol, 2013, 13(1): 187-91.
[6] Huang Y N, Zhao D D, Gao B, et al. Int J Mol Sci, 2012, 13(5):6320-33.
[7] Gao H, Huang Y N, Gao B, et al. Biosci Biotech Bioch, 2008, 72(2):601-3.
[8] Kim H J, Kim J, Kang K S, et al. Biomol Ther, 2014, 22(4):275-81.
[9] Nie G H, Li Z G, Lv Y Q, et al.Chinese Pharmaceutical Journal, 2001, 36 (8): 517-9.

HPLC of Chebulagic acid

HNMR of Chebulagic acid

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

Introduction/Overview

Chebulagic acid (CAS number: 23094-71-5), also known as gallic acid, is a natural polyphenolic compound isolated from the fruits of traditional medicinal plants and belongs to the tannin class. As a natural product with multi-target activity, succinic acid has attracted much attention in recent years due to its significant anti-inflammatory, antioxidant, and antiviral activities. Its unique double inhibition of COX-LOX provides a theoretical basis for its anti-inflammatory mechanism. At the same time, its inhibition on influenza virus M2 (S31N) mutant and novel coronavirus SARS-CoV-2 shows its broad prospects as a potential antiviral drug in the field of anti infection. In addition, the role of succinic acid in regulating oxidative stress-related signaling pathways provides a molecular basis for its application in antioxidant damage and related disease prevention and treatment. This article provides a systematic review of the chemical structure and physicochemical properties, plant sources and extraction methods, pharmacological activity and mechanism of action, pharmacological evaluation, and clinical application prospects of succinic acid. The aim is to provide scientific references for the in-depth research and drug development of this natural product.

Chemical structure and physicochemical properties

Hezibiphenylic acid is a complex polyphenolic compound with a molecular formula of C41H28O27 and a molecular weight of 890.66 Da. Its structural characteristics are mainly manifested by the binding of the core structure of biphenylic acid with multiple phenolic hydroxyl and ester bonds, forming a highly oxidized polyphenol network. This compound has 27 hydrogen bond acceptors, extremely high polarity (TPSA about 500 Å ²), a LogP value of -1.5, and exhibits strong hydrophilicity and low lipophilicity. Its high polarity and abundant hydroxyl groups endow succinic acid with excellent antioxidant capacity, but also pose challenges to its membrane permeability and bioavailability.

From the perspective of physical and chemical properties, hedonic acid is not easily able to pass through the blood-brain barrier, and currently has no significant hepatotoxicity, cardiotoxicity, or hERG channel inhibitory activity, indicating good safety. Its complex molecular structure and high polarity may limit its absorption and distribution in pharmacokinetics, but this also provides the possibility of targeting specific tissues or cells.

Plant sources and extraction methods

Hedyotis diffusa mainly exists in the fruit of Terminalia chabula Retz., which is a widely used medicinal herb in traditional Chinese medicine and Ayurvedic medicine. Its fruit is rich in various tannic compounds, including succinic acid, tannic acid, etc. In addition to Hezi, some plants in the Terminalia genus also contain this compound, but at lower levels.

The extraction method usually uses water extraction or alcohol extraction combined with liquid-liquid separation technology to ensure the integrity and activity of the compound. Common extraction techniques include:

1. Solvent extraction Using ethanol, water, or their mixed solvents as extraction agents, reflux or ultrasound assisted extraction is used to improve extraction efficiency.
2. Liquid-liquid separation Separate the extraction solution using organic solvents such as ethyl acetate and chloroform to remove impurities.
3. Column chromatography purification Using silica gel, C18 reverse phase column, etc. for separation and purification, high-purity succinic acid was obtained.
4. Optimization of preparation method In recent years, supercritical CO2 extraction and membrane separation technologies have also been attempted to improve yield and purity.

During the extraction process, attention should be paid to avoiding high temperature and strong acid-base conditions to prevent compound degradation. Purified succinic acid typically exists in the form of a brownish yellow powder, soluble in water and polar organic solvents.

Pharmacological activity research

anti-inflammatory effect

As a dual inhibitor of COX (cyclooxygenase) and LOX (lipoxygenase), succinic acid can effectively inhibit the synthesis of prostaglandins and leukotrienes, and alleviate inflammatory reactions. In vitro experiments have shown that succinic acid significantly inhibits COX-2 and 5-LOX enzyme activity, and reduces the expression of pro-inflammatory factors such as TNF - α, IL-1 β, and IL-6. In animal models, hedonic acid reduces edema and cell infiltration in inflammatory tissues, demonstrating good anti-inflammatory effects.

Antioxidant effect

Hedyotis diffusa exerts antioxidant protection by regulating various antioxidant enzymes and signaling pathways. It can activate the NFE2L2/NRF2 signaling pathway, promote the expression of downstream antioxidant enzymes SOD1, SOD2, CAT, GPX1, and HMOX1, clear reactive oxygen species (ROS), and alleviate cell damage caused by oxidative stress. This mechanism provides theoretical support for its potential application in oxidative damage related diseases such as neurodegenerative diseases, cardiovascular diseases, and chronic inflammation.

Antiviral effect

Hezibenzidine exhibits multiple activities in the field of antiviral activity. Firstly, as an effective inhibitor of the S31N mutant strain of influenza virus M2 protein, it can block the ion channel function of the virus and inhibit virus replication. Secondly, recent studies have found that chebula biphenyl acid has a significant inhibitory effect on the replication of SARS CoV-2 virus, with an EC50 of about 9.76 μ M, suggesting that chebula biphenyl acid is a potential candidate drug against COVID-19. In addition, hedonic acid also exhibits inhibitory activity against other viruses such as hepatitis B virus and herpes simplex virus, demonstrating its broad-spectrum antiviral potential.

Other pharmacological effects

Some studies have also reported that hedonic acid has anti-tumor, immune regulatory, and liver protective effects, but the relevant mechanisms still need further clarification.

Mechanism of action and molecular targets

The multi-target mechanism of action of succinic acid mainly includes:

1. COX-LOX dual inhibition By directly binding and inhibiting COX-2 and 5-LOX enzyme activity, reducing the synthesis of inflammatory mediators and blocking the inflammatory cascade reaction.
2. NFE2L2/NRF2 signal activation Inducing nuclear translocation of NFE2L2 transcription factor, activating expression of antioxidant enzyme genes, and enhancing cellular antioxidant defense ability.
3. Targeted inhibition of viral proteins：
4. Inhibition of influenza virus M2 (S31N) protein, blocking virus ion channel function, and inhibiting virus replication.
5. The inhibition of SARS-CoV-2 virus replication may involve interference from viral proteases or RNA dependent RNA polymerases, and the specific targets are yet to be further studied.
6. Regulating immune response Reduce inflammation and immune damage by inhibiting pro-inflammatory cytokines and regulating immune cell function.

Molecular docking and structural biology studies have shown that the polyphenolic hydroxyl groups of succinic acid form stable hydrogen bonds and hydrophobic interactions with the active sites of target proteins, enhancing binding affinity and supporting its multi-target pharmacological activity.

Evaluation of drug properties and pharmacokinetics

The pharmacological evaluation of succinic acid shows that it has certain advantages and challenges:

• High molecular weight (890.66 Da)This far exceeds the recommended upper limit of 500 Da by Lipinski's rules and may affect oral absorption and bioavailability.
• High polarity (TPSA 500 Å ²) and a large number of hydrogen bond acceptors (27)Not conducive to cell membrane penetration, limiting its oral absorption and tissue distribution.
• The LogP value is -1.5 This indicates that it has strong hydrophilicity, which may lead to slow absorption and poor biofilm permeability.
• Good safety There is no significant hepatotoxicity, cardiotoxicity, or hERG channel inhibition, which reduces potential drug safety risks.
• Poor blood-brain barrier penetration ability This limits its application in central nervous system diseases, but it is more advantageous for peripheral target therapy.

At present, there is limited pharmacokinetic data on hedonic acid, and preliminary studies suggest that its oral bioavailability is low, and its metabolic stability in vivo still needs further evaluation. To improve its pharmacokinetic performance, strategies such as nanocarriers, liposome encapsulation, and structural modification are being explored.

Clinical application prospects and prospects

As a natural multifunctional drug candidate molecule, succinic acid has broad clinical application potential:

1. Anti inflammatory diseases Suitable for adjuvant treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, especially in the presence of side effects of traditional nonsteroidal anti-inflammatory drugs (NSAIDs), the dual enzyme inhibitory effect and lower toxicity advantage of succinic acid are significant.
2. Antioxidant Protection In cardiovascular disease, neurodegenerative disease, diabetes and other oxidative stress related diseases, chebulabic acid can play a protective role as an antioxidant.
3. antiviral therapy: In view of the antiviral activity of influenza virus mutants and COVID-19, it provides new ideas for the treatment of acute viral infection. Especially in the context of increasingly serious virus resistance, the multi-target characteristics of natural products have unique advantages.
4. Potential for combination therapy Can be used in combination with existing drugs to enhance efficacy and reduce the risk of drug resistance.

Future research should focus on:

• Pharmacokinetic optimization and formulation development of succinic acid to improve its bioavailability and targeting.
• In depth analysis of its regulatory network on virus replication and inflammatory signaling pathways at the mechanistic level.
• Evaluate its safety, efficacy, and dosage range in preclinical and clinical trials, and promote its translational application.
• Explore its potential application value in immune regulation, anti-tumor and other therapeutic fields.

Conclusion

As a natural polyphenolic compound derived from traditional medicinal plants, hedonic acid exhibits broad pharmacological value and clinical application potential due to its unique COX-LOX dual inhibition, antioxidant, and antiviral activities. Despite the pharmacokinetic challenges posed by its large molecular weight and high polarity, it is expected to overcome these limitations with the assistance of modern drug design and delivery technologies. The pharmacological mechanism research, pharmacological optimization, and clinical evaluation of future systems will provide a solid foundation for the drug development of hedonic acid and promote it as a new generation of safe and effective natural drug candidate molecules.