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 No.: 23094-71-5), also known as heloleic acid, is a natural polyphenolic compound isolated from the fruits of traditional medicinal plants, classified as tannins. As a natural product with multi-target activity, Hezi biphenic acid has attracted attention in recent years for its remarkable anti-inflammatory, antioxidant, and antiviral activities. Its unique dual COX-LOX inhibitory effect provides a theoretical basis for its anti-inflammatory mechanism, and in the field of anti-infectivity, especially its inhibitory effects against the M2 (S31N) variant of influenza virus and the novel coronavirus SARS-CoV-2, it demonstrates broad prospects as a potential antiviral drug. Additionally, the role of Hezi biphenic acid in regulating oxidative stress-related signaling pathways provides molecular evidence for its application in antioxidant damage and related disease prevention and treatment. This paper will systematically review the chemical structure and physicochemical properties of Hezi biphenic acid, plant origin and extraction methods, pharmacological activity and mechanism of action, druggability evaluation, and clinical application prospects, aiming to provide scientific reference for in-depth research and drug development of this natural product.

Chemical structure and physicochemical properties

Hezi biphenic acid is a complex polyphenolic compound with a molecular formula of C41H28O27 and a molecular weight of 890.66 Da. Its structural features are mainly characterized by the combination of the biphenic acid core structure with multiple phenolic hydroxyl groups and ester bonds, forming a highly oxidized polyphenol network. This compound has 27 hydrogen bond receptors, extremely high polarity (TPSA about 500 Ų), and a LogP value of -1.5, demonstrating strong hydrophilicity and low lipid solubility. Its high polarity and abundant hydroxyl groups give Hezi biphenic acid excellent antioxidant capacity, but it also poses challenges to its membrane permeability and bioavailability.

From a physicochemical perspective, Hezi biphenic acid does not easily cross the blood-brain barrier, currently shows no significant hepatotoxicity, cardiotoxicity, or hERG channel inhibitory activity, and is relatively safe. Its complex molecular structure and high polarity may limit its pharmacokinetic absorption and distribution, but this also makes it possible to target specific tissues or cells.

Plant Origins and Extraction Methods

Hezi biphenic acid is mainly found in the fruit of Hezi (Terminalia chebula Retz.), which is widely used in traditional Chinese medicine and Ayurvedic medicine. Its fruit is rich in various tannin compounds, including hesolosinbiphenic acid and egastic acid. Besides Hezi, some Terminalia species also contain this compound, but in lower amounts.

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

1. Solvent extraction: Using ethanol, water, or their mixed solvents as extractors, reflux or ultrasound-assisted extraction improves extraction efficiency.
2. Liquid-liquid separation: Using organic solvents such as ethyl acetate and chloroform to separate the extract and remove impurities.
3. Column chromatography purification: Using silica gel, C18 reversed phase columns, etc., for separation and purification, high-purity Hezi biphenylic acid is obtained.
4. Preparation method optimization: In recent years, supercritical CO2 extraction and membrane separation technologies have also been attempted to improve yield and purity.

During extraction, avoid high temperatures and strong acidic or alkaline conditions to prevent compound degradation. Purified Hezi biphenic acid usually exists as a brownish-yellow powder, dissolved in water and polar organic solvents.

Pharmacological activity research

Anti-inflammatory effects

Hezibifenic acid, as a dual inhibitor of COX (cyclooxygenase) and LOX (lipoxygenase), can effectively suppress the synthesis of prostaglandins and leukotrienes, reducing inflammatory responses. In vitro experiments showed that hesol biphenic acid significantly inhibited the activities of COX-2 and 5-LOX enzymes, and reduced the expression of pro-inflammatory factors such as TNF-α, IL-1β, and IL-6. In animal models, hesolosinbiphenic acid reduced edema and cellular infiltration in inflamed tissues, demonstrating good anti-inflammatory effects.

Antioxidant effects

Hezi biphenic acid exerts antioxidant protective effects 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, scavenge reactive oxygen species (ROS), and reduce cell damage caused by oxidative stress. This mechanism provides theoretical support for its potential applications in diseases related to oxidative damage, such as neurodegenerative diseases, cardiovascular diseases, and chronic inflammation.

Antiviral effects

Hezi biphenic acid exhibits multiple activities in the antiviral field. First, as an effective inhibitor of the M2 protein S31N mutant strain of influenza virus, it can block the function of viral ion channels and suppress viral replication. Second, recent studies have found that Hezibifenic acid significantly inhibits SARS-CoV-2 viral replication, with an EC50 of about 9.76 μM, suggesting its potential value as a candidate drug against COVID-19. In addition, Hezi bifenic 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 Hezi biphenic acid has anti-tumor, immunomodulatory, and liver-protective effects, but the related mechanisms require further elucidation.

Mechanism of action and molecular targets

The main multi-target mechanisms of Hezi biphenic acid include:

1. Dual inhibition of COX-LOX: By directly binding to and suppressing the activities of COX-2 and 5-LOX enzymes, it reduces the synthesis of inflammatory mediators and blocks the inflammatory cascade.
2. NFE2L2/NRF2 signaling activation: Induces nuclear translocation of NFE2L2 transcription factor, activates antioxidant enzyme gene expression, and enhances cellular antioxidant defense capacity.
3. Viral protein targeted inhibition:
4. Inhibition of the influenza virus M2 (S31N) protein, blocking the function of viral ion channels and suppressing viral replication.
5. Inhibition of SARS-CoV-2 viral replication may involve interference from viral proteases or RNA-dependent RNA polymerase; specific targets require further research.
6. Regulating immune responses: By inhibiting pro-inflammatory cytokines and modulating immune cell function, it reduces inflammation and immune damage.

Molecular docking and structural biology studies show that the polyphenolic hydroxyl groups of Hezi biphenic 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.

Druggability evaluation and pharmacokinetics

The drug-worthiness evaluation of Hezi bifenic acid shows that it has certain advantages and challenges:

• The molecular weight is relatively large (890.66 Da), far exceeding the upper limit of 500 Da recommended by the Lipinski rule, which may affect oral absorption and bioavailability.
• High polarity (TPSA 500 Ų) and abundant hydrogen bond receptors (27) are unfavorable for cell membrane penetration, limiting oral absorption and tissue distribution.
• A LogP value of -1.5 indicates strong hydrophilicity, which may lead to slow absorption and poor biofilm permeability.
• It has good safety, with no significant hepatotoxicity, cardiotoxicity, or hERG channel suppression, reducing potential drug safety risks.
• Poor blood-brain barrier penetration limits its application in central nervous system diseases, but it is more advantageous for peripheral targeted therapy.

Currently, pharmacokinetic data on Hezi biphenic acid are limited, and preliminary studies suggest low oral bioavailability, and in vivo metabolic stability requires further evaluation. To improve its pharmacokinetic properties, strategies such as nanocarriers, liposome encapsulation, and structural modification are being explored.

Prospects and outlooks for clinical applications

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

1. Anti-inflammatory diseases: Suitable for adjunctive treatment of chronic inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, especially when traditional nonsteroidal anti-inflammatory drugs (NSAIDs) have side effects, where the dual enzyme inhibition and lower toxicity of hesolobhisic acid are evident.
2. Antioxidant protection: In diseases related to oxidative stress such as cardiovascular disease, neurodegenerative diseases, and diabetes, Hezi biphenic acid can act as an antioxidant to provide protection.
3. Antiviral therapy: Targeting the antiviral activity of influenza virus variants and COVID-19, it offers new approaches for treating acute viral infections, especially in the context of increasingly severe viral resistance, where the multi-target properties of natural products offer unique advantages.
4. Potential for combination therapy: Can be used in combination with existing drugs to enhance efficacy and reduce resistance risk.

Future research should focus on:

• Pharmacokinetic optimization and formulation development of Hezi bifenic acid to improve its bioavailability and targeting.
• Mechanistic analysis is conducted in depth of its regulatory networks for viral replication and inflammatory signaling pathways.
• Preclinical and clinical trials assess its safety, efficacy, and dosage range to promote its translational application.
• Explore its application value in other potential therapeutic areas such as immune regulation and anti-tumor treatments.

Conclusion

Hezi biphenic acid, a natural polyphenol compound derived from traditional medicinal plants, demonstrates broad pharmacological value and clinical application potential thanks to its unique COX-LOX dual inhibition, antioxidant, and antiviral activities. Although its large molecular weight and high polarity pose pharmacokinetic challenges, modern drug design and delivery technologies are expected to overcome these limitations. Future systematic pharmacological mechanism research, druggability optimization, and clinical evaluation will provide a solid foundation for the drug development of Hezi biphenic acid, promoting it to become a new generation of safe and effective natural drug candidate molecules.