Synonym name:
Catalogue No.: BP0638
Cas No.: 20831-76-9
Formula: C₁₆H₂₀O₉
Mol Weight: 356.327
Botanical Source: Widespread in the Gentianaceae, e.g. Swertia and Gentiana spp.

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:

Gentiopicroside has been developed into a novel traditional Chinese drug named gentiopicroside injection, and it was approved for the treatment of acute jaundice and chronic active hepatitis by SFDA.Gentiopicroside has analgesic, smooth muscle relaxing, antibacterial, and free radical scavenging activities, it exerts anti-inflammatory effects on experimental acute colitis through attenuating the expression levels of TNF-α, IL-1β, IL-6, iNOS and COX-2.

References:

J Ethnopharmacol. 2015 Aug 22;172:100-7.    

Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte.   

In traditional Chinese medicine, Gentiana macrophylla Pall have been prescribed for the treatment of pain and inflammatory conditions. In addition, it is a common Tibetan medicinal herb used for the treatment of tonsillitis, urticaria, and rheumatoid arthritis (RA), while the flowers of G. macrophylla Pall have been traditionally treated as an anti-inflammatory agent to clear heat in Mongolian medicine. The secoiridoid glycosides and their derivatives are the primary active components of G. macrophylla and have been demonstrated to be effective as anti-inflammatory agents. 

METHODS AND RESULTS:

Solvent extraction and D101 macroporous resin columns were employed to concentratethe Gentiopicroside. Gentiopicroside cytotoxicity was assessed by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; the toxicity of Gentiopicroside in chondrocytes was reconfirmed using Hoechst staining. Western blotting, reverse transcriptase-polymerase chain reaction (RT-PCR) and immunohistochemistry were utilized to explore the protective effects and mechanisms of Gentiopicroside prevents interleukin-1 beta induced inflammation response in rat articular chondrocyte. The MTT assay demonstrated that 50, 500, and 1,500 μg/mL of Gentiopicroside exhibited no significant toxicity to chondrocytes (P>0.05) after 24h. Using immunohistochemistry, ELISA, RT-PCR, Western blot method to explore the protective effect and mechanism of Gentiopicroside on chondrocytes induced by IL-1β. The results showed some pathways of IL-1β signal transduction were inhibited by Gentiopicroside in rat chondrocytes: p38, ERK and JNK. Meanwhile, Gentiopicroside showed inhibition in the IL-1β-induced release of MMPs while increasing Collagen type II expression. 

CONCLUSIONS:

The current study demonstrated that Gentiopicroside exhibited a potent protective effect on IL-1β induced inflammation response in rat articular chondrocyte. Thus, Gentiopicroside could be a potential therapeutic strategy for treatment of OA.    

Fitoterapia. 2003 Feb;74(1-2):151-4.    

Bioactivity of gentiopicroside from the aerial parts of Centaurium erythraea.   

Gentiopicroside (1), a secoiridoid glycoside isolated from the methanol extract of the aerial parts of Centaurium erythraea, has been assessed for antibacterial and free radical scavenging activities. General toxicity of 1 has also been determined by brine shrimp lethality bioassay.    

Fitoterapia. 2015 Apr;102:127-33.    

Effect of gentiopicroside on experimental acute pancreatitis induced by retrograde injection of sodium taurocholate into the biliopancreatic duct in rats.   

Gentiopicroside (otherwise known as Gentiopicrin), one of the main active ingredients from the traditional Chinese herb medicine Gentiana manshurica Kitag, presents the effect of attenuating acute pancreatitis in rats. 

METHODS AND RESULTS:

The experimental acute pancreatitis was made by retrograde injection of sodium taurocholate into the biliopancreatic duct in rats. Gentiopicroside was given orally and it markedly reduced the pancreatitis-evoked increase of serum amylase and lipase activity, decreased the pancreas mass/body mass index, tissue water content, TNF-α and IL-1β concentrations, and attenuated the histopathological changes and NF-κB p65 protein expression in pancreatic tissue.

CONCLUSIONS:

The results indicate that the function of Gentiopicroside on acute pancreatitis may be related to inhibiting the release of inflammatory mediators and NF-κB p65 protein expression.    

Chinese Traditional & Herbal Drugs, 2003, 34(9):814-6    

Studies on anti-inflammatory effect of gentiopicroside.   

To study the anti-inflammatory effect of Gentiopicroside extracted from Radix Gentianae Marrophyllae. 

METHODS AND RESULTS:

The models of auricular edema in mice induced by dimeth yl benzene, increased permeability of celiac blood capillary and body-twisting reaction induced by acetic acid, paw swelling induced by zymosan A, carrageenan a nd nystatin in rats or in mice were prepared. Then Gentiopicroside was given to the rats or mice by ig. Gentiopicroside inhibited th e auri cular edema, decreased the permeability of celiac blood capillary, reduced the p aw swelling induced by carrageenan and zymosan A, but not by nystation. 

CONCLUSIONS:

Gentiopicroside extracted from Radix Gentianae Marrophyllae, exhibits obvious anti-inflammatory effects.    

HPLC of Gentiopicrin

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. Among them, iridoid compounds have attracted much attention due to their structural diversity and wide range of biological activities. Gentiopicrin, also known as Gentiopicroside, CAS number 20831-76-9, is a typical representative of iridoid glycosides, mainly derived from Gentianaceae plants such as Gentianaceae（Gentiana scabra Bunge）、 Gentiana macrophylla（Gentiana macrophylla Pall, etc. As the main bitter component of these traditional medicinal plants, gentiopicroside is not only the pharmacological substance basis, but also an important quality marker. Modern pharmacological research has gradually progressed from traditional efficacy descriptions such as "clearing heat and dampness, purging liver and gallbladder fire" to the precise molecular mechanism level. Numerous studies have shown that gentiopicroside exhibits excellent anti-inflammatory activity and involves multiple key signaling pathways and molecular targets, making it highly promising in the treatment of inflammation related diseases. This article aims to systematically review the chemical properties, plant sources, pharmacological activities of gentiopicroside, especially its multi-target mechanism of anti-inflammatory effect, and evaluate and prospect its pharmacological properties and clinical application prospects, in order to provide comprehensive scientific references for the deep development and transformation research of this natural product.

Chemical structure and physicochemical properties

The chemical name of gentiopicroside is (5S, 6R, 8S, 9R, 10S) -6- (β - D-glucopyranosyl) -5,6,7,8,9,10-hexahydro-5,9-dihydroxy-8-methyl-1H, 5H-cyclopentano [c] pyran-1-one, with a molecular formula of C16H20O9 and a molecular weight of 356.3270. The core of its structure is a cyclohexene ether terpene parent nucleus of cyclopentanone pyranone, which is connected to a β - D-glucosyl group through a glycosidic bond at position C-1. This glycosidic structure is crucial for its water solubility and biological activity.

In terms of physical and chemical properties, gentiopicroside is a white or off white crystalline powder with an extremely bitter taste. Its calculated lipid water partition coefficient (LogP) is -0.9922, indicating its hydrophilicity. The topologically polar surface area (TPSA) is as high as 134.91 Å ², mainly attributed to the oxygen atoms on multiple hydroxyl and sugar groups in the molecule. Its water solubility data is 34.1458 mg/mL, confirming its good water solubility, which is beneficial for its development in aqueous formulations. However, higher polarity and TPSA also affect its transmembrane permeability, with a predicted "low" blood-brain barrier (BBB) permeability, indicating that it may have difficulty freely entering the central nervous system. In early safety screening, gentiopicroside showed no significant inhibitory effect on hERG potassium channels (hERG inhibition: No), indicating a low risk of cardiac toxicity. The Ames test result is 0.9 (usually considered negative if<1.5), indicating that there is no significant mutagenicity and providing positive data for its safety evaluation.

Plant sources and extraction methods

Gentiopicroside is a characteristic component and main active substance of Gentianaceae plants. In the traditional medical systems of China, Japan, and Europe, plants rich in gentiopicroside are widely used. Its main plant sources include:
1. gentian Longdan bitter glycoside is a core indicator for quality control of commonly used Chinese medicinal materials included in the Chinese Pharmacopoeia.
2. Large Leaf Gentian Similarly, it is an important traditional Chinese medicine used for rheumatism and rheumatism, and its content of gentiopicroside is also relatively high.
3. Swertia plants Like green leaf gallbladder（Swertia mileensis）Wait, it also contains abundant gentiopicroside.

Gentiopicroside mainly exists in the roots and rhizomes of plants. The extraction method has been continuously optimized with technological advancements
1. Traditional extraction method Water or different concentrations of ethanol (such as 30% -70%) are commonly used for heating reflux or immersion extraction. Ethanol concentration has a significant impact on extraction efficiency, and it is necessary to balance the polarity of gentiopicroside and the solubility of coexisting impurities.
2. Modern extraction techniques Including ultrasound assisted extraction, microwave-assisted extraction, and supercritical fluid extraction. These methods can significantly shorten extraction time, improve yield, and reduce solvent consumption. For example, ultrasound assisted extraction destroys plant cell walls through cavitation effect, which can more efficiently release target components.
3. Separation and purification The crude extract was subjected to column chromatography using macroporous adsorption resins (such as AB-8, D101), and its adsorption and molecular sieve effects were utilized to preliminarily enrich gentiopicroside. Further purification can be achieved through techniques such as silica gel column chromatography and preparative high-performance liquid chromatography to obtain high-purity monomers.

Pharmacological activity research

Gentiopicroside has a wide range of pharmacological activities, among which anti-inflammatory effects are the most prominent and profound. In addition, it also includes liver protection, analgesia, anti-tumor, and promotion of gastrointestinal motility.

1. anti-inflammatory activity This is the most widely studied activity of gentiopicroside. In various animal models of acute and chronic inflammation, such as carrageenan or acetic acid induced ear swelling in mice, cotton ball induced granuloma in rats, lipopolysaccharide induced systemic inflammation, and ulcerative colitis models, gentiopicroside has shown significant inhibitory effects. It can effectively reduce the levels of inflammatory mediators in the site of inflammation or serum.
2. Hepatoprotective effect Gentiopicroside has a protective effect on chemical (such as CCl4, acetaminophen) and immune liver injury, can reduce serum transaminase levels, alleviate liver tissue pathological damage, and its mechanism is related to anti-inflammatory, antioxidant, and inhibition of liver cell apoptosis.
3. Analgesic effect Its analgesic effect is partially independent of anti-inflammatory effects, and it has a relieving effect on pain caused by chemical stimulation (acetic acid writhing) and thermal stimulation (hot plate), suggesting that it may act on pain transmission pathways.
4. Antitumor activity Preliminary studies have shown that gentiopicroside has inhibitory effects on the proliferation of various tumor cell lines such as liver cancer, gastric cancer, and colon cancer, and can induce cell apoptosis. Its mechanism is related to the regulation of cell cycle and apoptosis related proteins.
5. Other activities This includes regulating gastrointestinal function, antidepressant like activity (although BBB penetration is low, it may act through peripheral central communication), and certain antioxidant effects.

Mechanism of action and molecular targets

The anti-inflammatory effect of gentiopicroside is not achieved through a single target, but through the synergistic action of multiple targets and pathways, forming a complex regulatory network. Based on the provided target information, its core mechanism can be summarized as follows:

1. Inhibition of NF - κ B signaling pathway This is the core mechanism of gentiopicroside's anti-inflammatory effect. Inflammatory stimuli activate the IKK complex, with IKBKB (I κ B kinase β) being a key subunit. Gentiopicroside can inhibit the activity of IKBKB, prevent the phosphorylation and degradation of I κ B protein, thereby causing the transcription factor RELA (i.e. p65) to remain in the cytoplasm and unable to enter the nucleus to initiate the transcription of pro-inflammatory genes (such as TNF, IL-6, NOS2).
2. Regulating the JAK/STAT signaling pathway Cytokines such as IL-6 bind to their receptors, activating JAK and subsequently phosphorylating STAT3. Phosphorylated STAT3 forms dimers and enters the nucleus, promoting the expression of inflammation related genes. Gentiopicroside can inhibit the production of IL-6 and the phosphorylation activation of STAT3, breaking the positive feedback loop of inflammation.
3. Regulating inflammasome activity The assembly of inflammasomes (such as NLRP3) activates CASP1 (cysteine protease-1), leading to the cleavage and maturation of IL-1 β and IL-18 precursors, triggering a strong inflammatory response. Gentiopicroside has been shown to inhibit the activation of CASP1, thereby reducing the release of mature IL-1 β.
4. Affects the synthesis of inflammatory mediators synthase：
   • NOS2 (inducible nitric oxide synthase)Gentiopicroside downregulates the expression of NOS2 and reduces the production of excessive inflammatory mediator nitric oxide.
   • PTGS1 (cyclooxygenase-1, COX-1）Unlike selective COX-2 inhibitors, gentiopicroside also has a certain regulatory effect on COX-1, which may affect the balance of prostaglandin mediators, but the specific mode of action needs further research.
5. Intervention in pain perception related ion channels：
   • TRPV1 (Transient receptor potential vanillic acid subtype 1)Participate in thermal pain and inflammation pain sensitization.
   • TRPA1 (Transient Receptor Potential Anchor Protein Subtype 1)Participate in chemical stimulation and cold pain sensation.
     Gentiopicroside may directly participate in its analgesic mechanism by regulating the activity of these channels.
6. Inhibit key pro-inflammatory factors Gentiopicroside can effectively reduce the expression and release of core pro-inflammatory cytokines such as TNF - α (encoded by the TNF gene) and IL-6, thereby upstream inhibiting the inflammatory cascade reaction.

In summary, gentiopicroside acts on key signaling nodes such as IKBKB, RELA, STAT3, CASP1, and regulates the expression of effector molecules such as TNF, IL-6, and NOS2, forming a multidimensional and networked anti-inflammatory system.

Evaluation of drug properties and pharmacokinetics

Although the in vitro activity of gentiopicroside is clear, its drug like and in vivo pharmacokinetic (PK) characteristics are the hurdles that it must overcome to enter clinical application.

• absorb As a hydrophilic glycoside, the oral absorption of gentiopicroside is the focus of its PK research. Studies have shown that its oral bioavailability is low. This is mainly attributed to: ① poor membrane permeability of intestinal epithelial cells (low LogP, high TPSA); ② May be hydrolyzed by gut microbiota into aglycones, which have properties different from glycosides; ③ There is a first pass enterohepatic effect. Formulation technologies such as phospholipid complexes, nanoemulsions, solid dispersions, etc. have been attempted to improve their oral absorption.
• distribution Gentiopicroside is widely distributed in the body, but as mentioned earlier, its predicted blood-brain barrier penetration ability is low, which limits its direct effect on central nervous system diseases. It is mainly distributed in blood rich tissues such as the liver and kidneys.
• Metabolism The main metabolic pathways of gentiopicroside in the body include hydrolysis (deglycosylation), oxidation, and binding reactions. The liver is its main metabolic site, and the cytochrome P450 enzyme system may be involved in its metabolism. Glycosides may be one of their active metabolites.
• excretion The prototype drug and its metabolites are mainly excreted through the kidneys in urine, and some are excreted through bile and feces.
• Comprehensive evaluation of drug properties From the perspective of the "Five Principles of Similar Drugs", gentiopicroside has a moderate molecular weight, but a low LogP and a high number of hydrogen bond donors and acceptors (TPSA), resulting in poor membrane permeability. Its advantage lies in the absence of hERG inhibition and Ames mutagenicity risk. The key to current research and development is to improve its oral absorption and bioavailability through structural modifications (such as prodrug preparation) or advanced drug delivery systems, while maintaining its multi-target anti-inflammatory properties.

Clinical application prospects and prospects

The clinical application prospects of gentiopicroside are broad, but the path still needs further exploration.

1. Potential indications：

   • Inflammatory bowel disease Based on its significant therapeutic effect on ulcerative colitis models and multi-target regulation of intestinal immune inflammation, it is a highly promising development direction.
   • Rheumatoid arthritis Its inhibitory effect on key joint inflammation pathways such as IL-6, STAT3, and TNF - α supports its use in the treatment of autoimmune arthritis.
   • hepatitis Combined with its clear hepatoprotective and anti-inflammatory effects, it can be used as an adjuvant therapy for acute or chronic hepatitis.
   • pain management Especially for inflammatory pain and visceral pain, the multi-target analgesic mechanism may be superior to single target analgesics.
   • skin disease Skin inflammatory diseases such as atopic dermatitis and psoriasis.

2. Development Challenges and Prospects：

   • structural optimization Structural modification of gentiopicroside while retaining its pharmacophore is an important topic in medicinal chemistry research to improve its lipid solubility, metabolic stability, and oral bioavailability.
   • Innovation in delivery system Developing targeted delivery systems based on nanotechnology (such as liposomes, polymer nanoparticles) or bioadhesive agents can increase the concentration at the lesion site and reduce systemic side effects.
   • Development of compound preparations As the main active ingredient of traditional Chinese medicine, studying the synergistic effect with other active ingredients (such as other cyclohexene ether terpenes in Gentiana macrophylla) and developing modern compound preparations may achieve better therapeutic effects.
   • In depth mechanism research Using chemical biology methods (such as molecular probes) to more accurately reveal their direct target proteins; Using systems pharmacology and network pharmacology methods, comprehensively elucidate its "multi-component multi-target multi-path" action network.
   • Clinical translational research After completing the preclinical safety evaluation (GLP toxicology) of the system, advancing standardized clinical trials is the final step in verifying its efficacy and safety.

Conclusion

As a natural iridoid glycoside with a long history of medicinal use, gentiopicroside has been fully validated by modern science for its powerful anti-inflammatory activity and clear multi-target mechanism of action. It exerts unique advantages in networked intervention of inflammatory diseases by regulating key signaling pathways such as NF - κ B, JAK/STAT, inflammasomes, and acting on multiple molecular targets ranging from IKBKB, STAT3 to TNF, IL-6, etc. Although it faces challenges such as poor oral absorption and low bioavailability in terms of drug development, this is precisely the direction that modern pharmacy and medicinal chemistry can focus on breaking through. With the continuous advancement of structural optimization, new drug delivery systems, and in-depth mechanism research, gentiopicroside is expected to transform from a traditional bitter ingredient into a modern drug or lead compound for the treatment of various inflammation related diseases such as inflammatory bowel disease and arthritis, providing a model for the innovative development of natural products.