Product name: Geniposidic acid
Synonym name: Premnosidic acid
Catalogue No.: BP0633
Cas No.: 27741-01-1
Formula: C₁₆H₂₂O₁₀
Mol Weight: 374.342
Botanical Source: Genipa americana (genipap), Garrya elliptica and Premna barbata
Physical Description: Powder
Type of Compound: Iridoids

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:
Geniposidic acid, one of the main active ingredients in Gardenia jasminoides J. Ellis (Rubiaceae), has anti-atherosclerotic effects, can protect vascular endothelium and reverse plaque formation in an atherosclerotic model.[1]
Geniposidic acid and geniposide have antitumor effects , play a role in an effective anticancer product with the ability to decrease undesirable radiation damage to the hematologic tissue after high dose irradiation.[2]
Geniposidic acid can protect against D-galactosamine and lipopolysaccharide-induced hepatic failure in mice.[3]
Geniposidic acid protects against anti-induced hepatotoxity and acute intrahepatic cholestasis, due to Fxr-mediated regulation of Bsep and Mrp2.[4]
Geniposidic acid has effects on the expression of MRP2 and BSEP in BRL-3A cells after FXR gene silencing mediated by si RNA.[5]

References:
[1] Yu G, Zi-Yu C, Xue L, et al. Pharm Biol, 2014, 53(2):1-6.
[2] Hsu H Y, Yang J J, Lin S Y, et al. Cancer Lett, 1997, 113(1-2):31-7.
[3] Kim S J, Kim K M, Park J, et al. J Ethnopharmacol, 2013, 146(1):271-7.
[4] Chen H, Huang X, Min J, et al. J Ethnopharmacol 2015, 179:197-207.
[5] Chen H, Shi S, Min J B, et al.China Journal of Traditional Chinese Medicine & Pharmacy, 2016,5.
[6] Peng M J, Zhang M, Liu J L, et al. Chinese Journal of Hospital Pharmacy, 2005, 25(04):300-2.

HPLC of Geniposidic acid

HNMR of Geniposidic acid

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

Introduction/Overview

As an important treasure trove for drug discovery, natural products continue to provide modern medicine with lead compounds with novel structures and diverse activities. Geniposidic acid (GA), a cyclic terpenoid glycoside, has undergone a profound evolution in its biological activity research from traditional heat clearing and detoxification effects to modern molecular pharmacology mechanisms since its discovery. Early research focused on its role as a precursor of geniposide in traditional Chinese medicines such as Gardenia and Eucommia ulmoides, as well as its weak anti-inflammatory and antioxidant properties. However, with the deepening of molecular target screening techniques and disease model research, the pharmacological value of geniposide has been redefined. In recent years, studies have revealed that it serves as a regulator of Farnesoid X receptor (FXR) and an effective activator of Sirtuin 6 (SIRT6), exhibiting multi-target and multi pathway regulatory potential in metabolism, inflammation, and tumor related diseases. Especially in major disease areas such as metabolic dysfunction associated fatty liver disease (MAFLD), drug-induced liver injury (DILI), inflammatory bowel disease (IBD), and colon cancer, geniposide has shown clear improvement effects. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, medicinal properties, and clinical application prospects of geniposide, 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 geniposide (CAS number: 27741-01-1) is (1S, 4aS, 7S, 7aS) -1- (β - D-glucopyranosyl) -7-hydroxymethyl-1,4-a, 5,7a - tetrahydrocyclopentano [c] pyran-4-carboxylic acid, with a molecular formula of C16H22O10 and a molecular weight of 374.34 g/mol. Its structure belongs to the class of iridoid glycosides, with the core being a cyclopentane pyran ring system. The C-1 position is connected to a β - D-glucosyl group through a glycosidic bond, the C-4 position is a carboxyl group (- COOH), and the C-7 position is a hydroxymethyl group (- CH2OH). The main difference between this structural feature and the homologous compound Geniposide is that the C-4 position is a carboxyl group rather than a methyl ester, which significantly affects its physicochemical properties and biological activity.

From the analysis of parameters related to drug properties, geniposide exhibits typical polar molecular characteristics. Its calculated lipid water partition coefficient (LogP) is -1.24, indicating its high hydrophilicity. The topologically polar surface area (TPSA) is as high as 166.14 Å ², mainly attributed to the abundant hydroxyl, carboxyl, and ether oxygen atoms in the molecule. The high TPSA and negative LogP values together determine its excellent water solubility, with a calculated value of approximately 49.34 mg/mL, which is beneficial for its development in aqueous formulations. However, these polar features also limit its passive transmembrane diffusion ability, resulting in a predicted "low" blood-brain barrier (BBB) permeability, suggesting that its direct effect on central nervous system diseases may be limited. In terms of preliminary safety prediction, this compound did not show significant hERG potassium channel inhibition risk (hERG inhibition: No), and the Ames test prediction result was negative (0.0), indicating a low potential mutagenic risk and providing a favorable starting point for subsequent safety evaluation.

Plant sources and extraction methods

Jingniping acid is relatively widely distributed in nature, mainly found in various medicinal plants such as Rubiaceae and Eucommia ulmoides, and is one of the important material bases for these plants to exert their medicinal effects.
1. Main plant sources：
* Gardenia jasminoides Ellis Gardenia fruit is the most famous source of geniposide acid. In Gardenia jasminoides, geniposide acid often coexists with higher levels of geniposide, and is a key intermediate in the biosynthesis pathway of geniposide, as well as one of its hydrolysis products.
* Eucommia ulmoides Oliv Eucommia ulmoides leaves and bark are rich in geniposide, which is considered one of the main active ingredients in Eucommia ulmoides for lowering blood pressure, antioxidation, and regulating metabolism.
* Chicken poop vine (Paederia scandens (Lour.) Merr.) Jingniping acid can also be detected in plants of the Rubiaceae family.
2. Extraction and Separation Methods：
The extraction of geniposide acid is mainly based on its polarity and solubility. Conventional methods use water or ethanol of different concentrations (such as 30% -70%) for heating reflux or ultrasound assisted extraction. Due to its good water solubility, the water extraction yield is high, but there are many impurities in the extract. The alcohol extraction method (especially low concentration ethanol) can reduce the dissolution of large polar impurities such as polysaccharides and proteins while ensuring extraction efficiency.
Column chromatography is commonly used to isolate and purify geniposide from crude extracts. Macroporous adsorption resins (such as D101, AB-8) are commonly used for initial enrichment, utilizing their adsorption differences with impurities such as sugars and pigments for purification. Further fine separation often relies on silica gel column chromatography, reverse phase silica gel column chromatography (such as ODS-C18), and preparative high-performance liquid chromatography (HPLC). In recent years, liquid-liquid distribution chromatography techniques such as high-speed countercurrent chromatography (HSCCC) have also been applied to the efficient preparation and separation of geniposide due to their advantages of avoiding irreversible adsorption and high recovery rate.
3. Analysis and identification：
The qualitative and quantitative analysis of geniposide in extracts or products is mainly carried out using high-performance liquid chromatography ultraviolet detection (HPLC-UV) or high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS). It has terminal absorption in the ultraviolet region, and the commonly used detection wavelength is around 238 nm. Mass spectrometry can provide its molecular ion peak [M-H] ⁻ m/z 373.1 and characteristic fragment ion information for confirming the structure.

Pharmacological activity research

Jingniping glycoside acid has a wide range of pharmacological activities, and its research has penetrated from the organ and tissue level to the cellular and molecular level, especially showing significant potential in the prevention and treatment of metabolic diseases, inflammatory diseases, and tumors.

1. Liver protection and anti metabolic disease activity：
   • Improving metabolic dysfunction associated fatty liver disease (MAFLD/MASH)This is currently one of the most highly anticipated activities of geniposide. In various high-fat diet induced or chemically induced animal models, geniposide can significantly reduce liver lipid accumulation (triglycerides and cholesterol), alleviate hepatocyte ballooning and inflammatory infiltration, and improve liver function indicators (such as ALT and AST). Its function is not limited to "protecting the liver", but also lies in regulating energy metabolism and inflammation from the fundamental links.
   • Drug induced liver injury (DILI)Research has shown that geniposide has a protective effect on acute liver injury caused by acetaminophen (APAP), carbon tetrachloride (CCl ₄), etc. It can reduce oxidative stress levels, inhibit liver cell apoptosis and necrosis.
2. Anti inflammatory and intestinal protective activity：
   • Relieve colitis In mouse colitis models induced by dextran sulfate sodium (DSS) or trinitrobenzenesulfonic acid (TNBS), gavage of geniposide can significantly alleviate disease activity index, improve colon shortening and histopathological damage. Its mechanism is closely related to directly inhibiting excessive inflammatory response of intestinal mucosa and regulating the ecological balance of intestinal microbiota.
   • Regulating gut microbiota Jingniping glycoside acid, as a glycoside compound that is not easily absorbed by the upper gastrointestinal tract, can directly reach the colon and be partially metabolized by intestinal microbiota. Research has found that it can promote the growth of beneficial bacteria such as lactobacilli and Akkermansia, inhibit the proliferation of opportunistic pathogens, increase the production of short chain fatty acids (SCFAs), thereby strengthening the intestinal barrier and exerting an overall regulatory effect on the "gut liver axis" or "gut immune axis".
3. Antitumor activity (with a focus on colon cancer)：
   Jingniping glycoside acid exhibits inhibitory effects on proliferation and induces apoptosis in various tumor cell lines, among which research on colon cancer is more systematic. It can inhibit the in vitro proliferation, migration, and invasion ability of human colon cancer cells (such as HCT-116, SW480). In animal transplant tumor models, certain tumor growth inhibition effects can also be observed. Its anti-tumor effect involves multiple signaling pathways rather than a single target action.
4. Other activities：
   In addition, studies have reported that geniposide has antioxidant, antihypertensive (possibly related to the traditional antihypertensive effects of Eucommia ulmoides), and mild neuroprotective activities, but the depth and mechanism of research in these areas are relatively limited.

Mechanism of action and molecular targets

The multiple pharmacological activities of geniposide stem from its precise regulation of multiple key molecular targets and signaling pathways, and its mechanism of action network is becoming increasingly clear.

1. As an FXR regulator, regulating bile acid and lipid metabolism：
   The farnesol X receptor (FXR) is a member of the nuclear receptor superfamily and plays a central role in maintaining bile acid, lipid, and glucose homeostasis. Jingniping acid has been confirmed to be a regulator of FXR. Structural biology and molecular docking simulations show that it can directly bind to the Ser332 and His447 sites of the FXR ligand binding domain (LBD). This binding drives conformational changes in FXR, promoting its translocation from the cytoplasm to the nucleus. In the nucleus, activated FXR forms heterodimers with retinol X receptor (RXR), recruiting co activators (such as SRC-1) to bind to the FXR response element (FXRE) of the target gene promoter, thereby regulating gene transcription. The downstream effects include:

   • Promote the expression of small heterodimeric chaperone (SHP)SHP can inhibit the transcription of cholesterol 7 α - hydroxylase (CYP7A1), which is the rate limiting step in bile acid synthesis, thereby negatively feedback regulating bile acid synthesis and reducing bile acid toxicity.
   • Induction of Bile Salt Output Pump (BSEP) Expression Promote the excretion of bile acids from liver cells to bile ducts.
   • Regulating genes related to lipid metabolism Such as affecting fatty acid synthase (FAS), sterol regulatory element binding protein-1c (SREBP-1c), etc., reducing hepatic lipid synthesis. By activating FXR, geniposide improves cholestasis and hepatic steatosis through multiple pathways.

2. As an activator of SIRT6, it improves metabolism and inflammation：
   Silencing Information Regulatory Factor 6 (SIRT6) is an NAD ⁺ - dependent deacetylase involved in regulating glucose metabolism, fat metabolism, inflammation, and genomic stability. Jingniping glycoside acid has been identified as a natural activator of SIRT6. Activating SIRT6 can bring multiple benefits:

   • Improving insulin sensitivity and glucose metabolism SIRT6 deacetylates and inhibits glycolysis related transcription factors HIF-1 α and MYC, suppressing liver glycolysis and fat production.
   • anti-inflammatory SIRT6 downregulates inflammatory factors such as TNF - α, IL-1 β, and IL-6 by deacetylating histone H3K9 and inhibiting the expression of target genes for pro-inflammatory transcription factors such as NF - κ B.
   • In MAFLD Jingniping acid activates SIRT6, synergistically regulates lipid metabolism, and inhibits liver inflammation, which is the key mechanism for improving MASH phenotype.

3. Multi target action network in the treatment of colon cancer：
   The mechanism of geniposide in the treatment of colon cancer presents multi-target and networked characteristics, involving multiple aspects such as proliferation, apoptosis, inflammation, and multidrug resistance

   • Inducing apoptosis and inhibiting proliferation By activating the AMPK (PRKAA1) signaling pathway, inhibiting mTOR, and regulating the cell cycle; Simultaneously regulating the balance of Bcl-2 family proteins, downregulating anti apoptotic proteins Bcl-2 and Mcl-1, promoting the expression of pro apoptotic proteins, and inducing cancer cell apoptosis.
   • Inhibiting inflammation and survival signals Effectively inhibit the abnormal activation of transcription factors STAT3 and NF - κ B (RELA), thereby downregulating their regulated pro proliferative, anti apoptotic, and pro metastatic genes (such as Cyclin D1, Survivor, MMPs).
   • Overcoming the potential of multidrug resistance Research has shown that it can downregulate the expression of multidrug resistance protein ABCB1 (P-gp), which may help reverse chemotherapy resistance in colon cancer.
   • Affects other targets It may also affect arachidonic acid metabolism by inhibiting 5-lipoxygenase (ALOX5), or indirectly affect pathways such as MAPK (ERK1/2). Its potential effect on Topoisomerase I (TOP1) also suggests the possibility of interfering with DNA replication.

4. Integration of anti-inflammatory mechanisms：
   In colitis and hepatitis models, the anti-inflammatory effect of geniposide is the combined result of its FXR activation, SIRT6 activation, and direct inhibition of NF - κ B and MAPK inflammatory pathways. The regulatory effect of gut microbiota further amplifies its systemic anti-inflammatory benefits by increasing SCFAs, reducing endotoxin entry into the bloodstream, and systematically inhibiting pathways such as TLR4/NF - κ B.

Evaluation of drug properties and pharmacokinetics

Although geniposide has shown good biological activity in preclinical studies, its pharmacological properties, especially pharmacokinetic properties, are a key step that must be faced in its drug conversion process.

1. Absorption, distribution, metabolism, excretion (ADME)：
   • absorb Jingniping glycoside has high polarity and poor lipid solubility, suggesting that its oral bioavailability may be low. The prototype drug may be mainly absorbed through the paracellular pathway of small intestinal epithelial cells or limited absorption through transporters. Most oral doses may directly reach the colon and be metabolized by the gut microbiota. β - glucosidase in the gut microbiota can hydrolyze its glycosidic bonds to produce aglycones (geniposide) and glucose, which may have different absorption and activity characteristics.
   • distribution Due to its high hydrophilicity and low BBB permeability, it is predicted that it is mainly distributed in blood rich tissues such as the blood, liver, and kidneys, making it difficult to enter the central nervous system. Local concentrations may reach high levels in the liver and intestines, which is consistent with the target organ localization for treating liver and intestinal diseases.
   • Metabolism In addition to gut microbiota metabolism, it may undergo II binding reactions (such as glucuronidation and sulfation) in the liver. At present, there is insufficient research on its detailed in vivo metabolite profile and activity.
   • excretion The prototype and its metabolites may be mainly excreted from urine through the kidneys, and some may also be excreted through bile, indicating the possibility of enterohepatic circulation.
2. Challenges and optimization strategies for drug development：
   • challenge Low oral bioavailability is the biggest challenge for the development of geniposide as an oral formulation. In addition, the cyclohexene ether terpene skeleton and glycosidic bonds in its chemical structure may be unstable in acidic or enzymatic environments.
   • Optimization Strategy：
     • Prodrug design Esterify the carboxylic acid at C-4 position or the hydroxyl group at C-7 position to prepare precursor drugs with higher lipid solubility (such as alkyl esters), in order to improve membrane permeability and oral absorption, and release the original drug through esterase hydrolysis in vivo.
     • Formulation technology Using drug delivery systems such as solid dispersions, nanocrystals, liposomes, and self microemulsions to improve solubility and dissolution rate, or promote intestinal lymphatic absorption, bypassing the first pass effect.
     • Structural modification On the premise of retaining the pharmacophore, appropriate modifications should be made to the sugar moiety or ring system to balance hydrophilicity and oleophilicity and improve ADME properties.
3. Preliminary evaluation of safety：
   The existing preclinical toxicology data is limited. Based on its natural product properties and long-term history of traditional Chinese medicine application (as a component of Gardenia and Eucommia ulmoides), it is speculated that its acute toxicity may be relatively low. Computer predictions suggest that there is no significant risk of hERG inhibition and mutagenicity, but comprehensive preclinical safety evaluations (such as acute toxicity, chronic toxicity, reproductive toxicity, etc.) still need to be systematically conducted.

Clinical application prospects and prospects

The unique dual target (FXR/SIRT6) properties and multi effect pharmacological effects of geniposide acid provide broad prospects for its application in multiple disease fields, but also face many challenges.

1. Potential clinical application directions：
   • Metabolic dysfunction associated fatty liver disease (MAFLD/MASH)This is the most promising direction. At present, there is no approved specific drug for MASH worldwide. Jingniping glycoside acid intervenes in the core mechanism of diseases through dual pathways of regulating bile acid, lipid metabolism, and inhibiting inflammation by synergistically activating FXR and SIRT6, which may be more advantageous than single target drugs. It is expected to be developed as a first-line or adjuvant drug for oral treatment of MASH.
   • Inflammatory bowel disease (IBD)Its powerful local anti-inflammatory and microbiota regulating effects make it suitable for the treatment of IBD such as ulcerative colitis. It can be considered to develop colon targeted formulations (such as pH dependent or enzyme triggered drug release coated tablets), allowing drugs to be released locally in the colon, improving efficacy and reducing systemic side effects.
   • Chemotherapy prevention and adjuvant therapy for colon cancer Given its multi-target anti-tumor properties and ability to regulate the intestinal microenvironment, geniposide may be used for chemoprevention in high-risk populations of colon cancer, or in combination with existing chemotherapy drugs, to enhance sensitivity and reduce toxicity (such as alleviating chemotherapy-induced enteritis).
   • Prevention and treatment of drug-induced liver injury (DILI)As a hepatoprotective drug, it is used to prevent or treat liver damage caused by specific drugs (such as anti tuberculosis drugs, antipyretic analgesics).
2. Future research focus and challenges：
   • In depth mechanism research Further clarification is needed on the precise molecular details of its activation of FXR and SIRT6, as well as the cross-talk between these two pathways. The specific target priority of its role in tumors needs to be clarified.
   • Systematic pharmacokinetic study Urgent need for standardized animal (rat, dog, etc.) and human ADME research to clarify their absolute bioavailability, major metabolites, tissue distribution, and excretion pathways, providing a basis for formulation design.
   • Preclinical development and formulation research A complete GLP toxicology evaluation must be conducted. The development of formulations is a key breakthrough point, and feasible solutions that can significantly improve their oral bioavailability need to be explored.
   • clinical translation Ultimately, rigorous clinical trials need to be designed to validate its effectiveness and safety in the target indications, primarily MASH and IBD.
   • Source and Sustainability Although it can be extracted from plants, exploring green biological preparation technologies such as microbial fermentation synthesis or plant cell culture is also of great significance to ensure stable quality and sustainable supply.

Conclusion

Jingniping glycoside, as a natural iridoid glycoside derived from traditional Chinese medicine, has transformed from a common phytochemical component into a modern molecular probe and potential drug lead compound that acts on key targets of FXR and SIRT6. Its outstanding performance in improving metabolic liver disease, intestinal inflammation, and related tumors reflects the unique advantages of natural product multi-component and multi-target synergistic therapy for complex diseases. Despite facing challenges in drug formulation, especially in oral absorption, these challenges are expected to be gradually overcome through the empowerment of modern pharmaceutical chemistry, pharmacology, and pharmacology technologies. In the future, with deeper analysis of its molecular mechanism, systematic optimization of pharmacokinetic properties, and advancement of clinical research, geniposide is highly likely to be successfully transformed from an excellent research tool molecule into an innovative drug for the treatment of major chronic diseases such as MAFLD and IBD, achieving a magnificent transformation from traditional wisdom to modern medicine and contributing new strength to human health.