Product name: Saikosaponin I
Synonym name:
Catalogue No.: BP3914
Cas No.: 103629-71-6
Formula: C₄₈H₇₈O₁₇
Mol Weight: 927.135
Botanical Source:
Type of Compound:

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
Inquire for bulk scale.

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

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

Introduction/Overview

Natural products, as an important source of drug discovery, have always played an irreplaceable role in the long struggle between humans and diseases. Among the numerous natural compounds with biological activity, those from the Apiaceae family belong to the genus Bupleurum（Bupleurum L. The triterpenoid saponins in plants have attracted much attention due to their extensive pharmacological activities and long clinical application history. Chaihu, as one of the most commonly used herbs in traditional Chinese medicine, was first recorded in the "Shennong Bencao Jing" and is listed as a top-grade herb. It has the effects of harmonizing the exterior and interior, soothing the liver and relieving depression, and elevating yang qi. Modern pharmacological research has confirmed that Chaihu and its active ingredients exhibit significant activities in antipyretic, anti-inflammatory, hepatoprotective, antiviral, immunomodulatory, and anti-tumor aspects.

Saikosaponins are the main active ingredient group in Bupleurum chinense, belonging to the oleanane type pentacyclic triterpenoid saponins. Since the 1960s, over 100 monomers of saikosaponin have been isolated and identified, among which saikosaponin a, c, and d are the most extensively studied representative components. However, with the advancement of separation techniques and structural identification methods, some trace saponins with low content but unique biological activity have gradually entered the field of researchers. Saikosaponin I (SSI) is one of them. This compound was first synthesized in 1986 Bupleurum falcatum L. The unique chemical structure and potential pharmacological activity of it, especially its enormous potential in the field of antiviral research in recent years, have made it an emerging hotspot in natural product pharmacology research.

This article aims to provide a systematic review of the research status of saikosaponin I, covering its chemical structure and physicochemical properties, plant sources and extraction methods, pharmacological activity, mechanism of action, drug evaluation, and clinical application prospects, in order to provide comprehensive scientific basis for the in-depth development and utilization of this compound.

Chemical structure and physicochemical properties

The chemical structure of saikosaponin I belongs to the oleane type pentacyclic triterpenoid saponin. Its aglycone is a derivative of epoxyoleanolic acid. Specifically, its parent nucleus structure forms a double bond between the C-11 and C-13 positions of oleanolic acid, and a unique ether bridge between the C-13 and C-28 positions, forming a 13,28-epoxyoleanane skeleton. This characteristic structure is one of the key distinguishing features of saikosaponin from other triterpenoid saponins.

In the sugar chain, saikosaponin I is connected to a straight chain oligosaccharide chain consisting of two sugar units at position C-3. Normally, this sugar chain is composed of β - D-glucose and β - D-fucose, where fucose is directly connected to the hydroxyl group at position C-3 of the glycoside, while glucose is connected to fucose through a (1 → 3) glycosidic bond. In addition, there may be an acetyl group (- OAc) attached to the C-16 position, which further increases the complexity of its structure. Its specific chemical structural formula can be expressed as: 3 β, 16 β, 23,28-tetrahydroxy-13,28-epoxyolean-11-ene-3-O - β - D-glucopyranosyl - (1 → 3) - β - D-fucosyl glycoside. Its molecular formula is C ₄₈ H ₇₈ O ₁₇, and its molecular weight is 927.1350 g/mol.

From the perspective of physicochemical properties, saikosaponin I exhibits typical saponin characteristics. It is a white or off white amorphous powder with certain hygroscopicity. Its lipid water partition coefficient (LogP) is 2.5658, indicating that it has a certain degree of lipophilicity, but also a certain degree of hydrophilicity, which is related to the presence of multiple hydroxyl and sugar groups in its molecule. Its total polar surface area (TPSA) is as high as 277.91 Å ², mainly attributed to the large number of hydroxyl and ether oxygen atoms in the molecule. A high TPSA value usually indicates that the compound is difficult to passively diffuse through the cell membrane, especially the blood-brain barrier (BBB). Its solubility has been calculated to be 0.0534 mg/mL, which belongs to the category of slight solubility. In addition, the compound may have weak end absorption under ultraviolet light, and the conjugated system in its structure (such as 11,13-ene) makes it detectable at specific wavelengths. These physicochemical properties lay the foundation for its subsequent extraction, separation, analysis, and biological activity research.

Plant sources and extraction methods

Chaihu saponin I was originally derived from plants of the Bupleurum genus in the Umbelliferae family Bupleurum falcatum L. Separated from (Chaihu Mishima). However, as research deepened, it was found that the compound was not B. falcatum Unique to it. It is widely present in the roots and rhizomes of various Bupleurum plants, including but not limited to Bupleurum chinense DC. (Bupleurum chinense)Bupleurum scorzonerifolium Willd. (South Chaihu)Bupleurum marginatum Wall. ex DC. (Zhuye Chaihu) and Bupleurum kaoi Liu, Chao&Chuang (Gao's Chaihu) and others. There are significant differences in the content of saikosaponin I among different species, origins, harvest seasons, and medicinal parts (roots, stems, leaves). Usually, the content in the roots is higher than that in the aboveground parts, and as the plant grows for more years, its accumulation also changes. It is worth noting that the content of saikosaponin I in plants is usually much lower than that of the main components such as saikosaponin a, c, and d, and it belongs to trace or secondary metabolites, which poses certain challenges for its large-scale preparation.

For the extraction of saikosaponin I, the classic solvent extraction method combined with modern separation and purification techniques is currently mainly used. The selection of extraction solvent is crucial. Given its slight solubility in water and easy solubility in polar organic solvents such as methanol and ethanol, methanol or different concentrations of ethanol (such as 70% ethanol) are often used as extraction solvents. The extraction methods include:

1. Traditional impregnation method and percolation method Easy to operate, but time-consuming, requires a large amount of solvent, and has relatively low extraction efficiency.
2. reflux extraction: is currently the most commonly used method in laboratories and industrial production. Extract Chaihu powder by refluxing with methanol or ethanol several times, combine the extracts, and recover the solvent under reduced pressure to obtain the crude extract of total saponins. This method is highly efficient, but high temperatures may cause degradation or structural transformation of some thermally unstable saponins.
3. Ultrasonic assisted extraction method Utilizing the cavitation effect and mechanical vibration of ultrasound to accelerate solvent penetration and effective ingredient dissolution. This method has the advantages of short extraction time, controllable temperature, and high efficiency, and is particularly suitable for protecting thermosensitive components.
4. Microwave assisted extraction method Using microwave energy to selectively heat polar molecules, the temperature inside the cell rapidly increases, the pressure increases, causing the cell wall to rupture, thereby promoting the release of target components. This method has a fast extraction speed, but requires high equipment requirements.

After obtaining the crude extract of total saponins, further separation and purification are required to obtain high-purity monomers of saikosaponin I. Common separation and purification strategies include:

• Liquid-liquid extraction Using different solvents (such as petroleum ether, ethyl acetate, n-butanol) for fractional extraction of total saponins to remove lipid soluble impurities and water-soluble impurities such as sugars. The n-butanol layer usually accumulates most of the saponins.
• Macroporous adsorption resin column chromatography This is a classic method for separating saponin components. The commonly used resin types include D101, AB-8, HPD100, etc. By gradient elution using ethanol water systems of different concentrations, total saponins can be preliminarily separated according to their polarity and the target saponin components can be enriched.
• Silica gel column chromatography The use of silica gel adsorption and solvent systems such as chloroform methanol water for isocratic or gradient elution is the core method for achieving saponin monomer separation. Due to the similarity in structure between saikosaponin I and other saponins, repeated silica gel column chromatography is often required to obtain the pure product.
• High performance liquid chromatography (HPLC)Especially preparative HPLC is the ultimate method for obtaining high-purity monomers of saikosaponin I. By using a reverse phase C18 column with acetonitrile water or methanol water as the mobile phase, combined with a UV detector or evaporative light scattering detector (ELSD), efficient separation and purification of trace components in complex mixtures can be achieved.

Pharmacological activity research

In recent years, there has been an increasing amount of research on the pharmacological activity of saikosaponin I, which has shown potential biological activity in multiple fields such as antiviral, anti-inflammatory, hepatoprotective, and anti-tumor effects. Among them, the research on antiviral effects is the most prominent.

1. Antiviral activity

This is currently the most concentrated area of research on saikosaponin I. Research has shown that SSI has inhibitory effects on various viruses.

• Anti herpes simplex virus (HSV)Multiple in vitro experiments have confirmed that SSI can effectively inhibit the replication of HSV-1 and HSV-2. Its mechanism of action may involve multiple steps, including direct inactivation of virus particles, inhibition of virus adsorption and penetration into host cells, and interference with virus DNA replication and late protein synthesis.
• Anti human immunodeficiency virus (HIV)SSI has been reported to have anti-HIV-1 activity. Its potential targets may include inhibiting the activity of HIV-1 reverse transcriptase (RT) and integrase (INT), as well as blocking virus entry into target cells by downregulating the expression of co receptors such as CCR5 and CXCR4. This makes it a potential anti HIV lead compound.
• Anti Cytomegalovirus (HCMV)Preliminary studies have shown that SSI also has a certain inhibitory effect on HCMV replication, and its mechanism may be related to the inhibition of viral DNA polymerase (UL54) or early protein expression.
• Anti other viruses In addition, SSI has been reported to have a certain inhibitory effect on influenza virus, respiratory syncytial virus (RSV), etc., demonstrating broad-spectrum antiviral potential.

2. Anti inflammatory activity

Inflammation is a common pathological basis for many diseases, such as hepatitis and nephritis. SSI inherits the typical anti-inflammatory properties of the saikosaponin family. Research has shown that SSI can significantly inhibit the production of nitric oxide (NO), prostaglandin E2 (PGE2), as well as pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α) and interleukin-6 (IL-6) in macrophages stimulated by lipopolysaccharide (LPS). Its mechanism of action is closely related to the inhibition of the activation of nuclear factor kappa B (NF - κ B) and mitogen activated protein kinase (MAPK) signaling pathways. By blocking these key inflammatory signaling pathways, SSI can effectively alleviate inflammatory responses.

3. Liver protective activity

Chaihu is an essential medicine in traditional Chinese medicine for treating liver disease. SSI, as one of the active ingredients of Bupleurum chinense, also exhibits significant hepatoprotective effects. In animal models of acute liver injury induced by carbon tetrachloride (CCl ₄) or D-galactosamine (D-GalN), SSI pretreatment can significantly reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, alleviating pathological damage to liver tissue such as necrosis and steatosis. Its hepatoprotective mechanism may be related to its antioxidant, anti-inflammatory, and inhibition of liver cell apoptosis. SSI can eliminate free radicals, increase the activity of endogenous antioxidant enzymes in the liver (such as superoxide dismutase (SOD) and glutathione peroxidase (GSH Px)), and inhibit the activation of hepatic stellate cells, thereby exerting its potential in anti liver fibrosis.

4. Antitumor activity

Some preliminary studies have explored the anti-tumor activity of SSI. The results showed that SSI could inhibit the proliferation of many human cancer cell lines (such as HepG2, A549 and MCF-7 of breast cancer). Its mechanism of action may involve inducing cell cycle arrest (such as G0/G1 phase arrest) and promoting cell apoptosis (through the mitochondrial pathway or death receptor pathway). However, compared to classic anti-tumor saponins such as saikosaponin d, SSI has relatively weaker cytotoxicity, but its toxicity to normal cells is also lower, demonstrating a certain degree of selectivity. In the future, SSI may be used as a low toxicity adjuvant therapy drug or as a lead compound for structural modification.

Mechanism of action and molecular targets

The pharmacological activity of saikosaponin I is the result of its interaction with multiple molecular targets. Its mechanism of action exhibits the characteristics of multi-target and multi pathway.

1. Mechanism of antiviral action

The antiviral mechanism of SSI is complex and not a single target. According to existing research, its potential targets include:

• Virus envelope proteins and host receptors For HSV, SSI may directly interact with the virus envelope glycoprotein gD or gB, interfering with the binding of the virus to receptors on the host cell membrane, thereby blocking the virus's adsorption and membrane fusion processes. For HIV, SSI may downregulate the expression of co receptors CCR5 and CXCR4 on the host cell surface, thereby preventing HIV-1 from entering the cell.
• Viral enzymes SSI can inhibit the activity of key enzymes in the lifecycle of viruses. For example, it can inhibit HSV thymidine kinase (TK) and DNA polymerase (UL42/UL54), thereby interfering with the synthesis of viral DNA. For HIV, it can inhibit the activity of HIV-1 protease (HIV1-PR) and integrase (INT). In addition, it may also affect the function of HCMV DNA polymerase (UL54) and early regulatory proteins (such as ICP27).
• Host cell signaling pathway SSI may exert antiviral effects by regulating the innate immune response of host cells. For example, it may establish antiviral status by activating the interferon regulatory factor (IRF) pathway, inducing the expression of interferon and interferon stimulated genes (ISGs).

2. Anti inflammatory mechanism

The anti-inflammatory effect of SSI is mainly achieved through the regulation of key inflammatory signaling pathways.

• NF - κ B pathway At rest, NF - κ B binds to its inhibitory protein I κ B and exists in an inactive form in the cytoplasm. When stimulated by inflammation such as LPS, I κ B kinase (IKK) is activated, leading to phosphorylation and degradation of I κ B, releasing NF - κ B. Activated NF - κ B enters the nucleus and initiates transcription of various pro-inflammatory genes, such as TNF - α, IL-6, iNOS, COX-2. SSI can inhibit the activity of IKK, reduce the degradation of I κ B, and thus block the nuclear translocation and transcriptional activity of NF - κ B.
• MAPK pathway The MAPK family includes ERK, JNK, and p38 MAPK. These kinases also play important roles in inflammatory responses. SSI can inhibit LPS induced phosphorylation of p38 MAPK and JNK, thereby reducing the production of downstream inflammatory mediators.
• Myeloperoxidase (MPO)MPO is a marker enzyme for neutrophil activation, involved in oxidative stress and inflammatory damage. SSI has been reported to inhibit the activity of MPO, which may be another pathway of its anti-inflammatory effect.

3. Liver protective mechanism

• anti-oxidative stress SSI can directly eliminate reactive oxygen species (ROS) and reactive nitrogen species (RNS), and upregulate the activity of antioxidant enzymes (such as SOD, GSH Px, catalase CAT) in the liver, enhancing the body's ability to eliminate free radicals and thereby reducing oxidative stress damage to liver cells.
• anti-apoptotic SSI can regulate mitochondrial membrane potential, inhibit the release of cytochrome C, and regulate the expression of Bcl-2 family proteins (such as upregulating anti apoptotic protein Bcl-2 and downregulating pro apoptotic protein Bax), thereby inhibiting the activation of Caspase cascade reaction and ultimately inhibiting liver cell apoptosis.
• Anti liver fibrosis SSI may exert anti liver fibrosis effects by inhibiting the transforming growth factor - β 1 (TGF - β 1)/Smad signaling pathway, suppressing the activation and proliferation of hepatic stellate cells, reducing the deposition of extracellular matrix (such as collagen).

Evaluation of drug properties and pharmacokinetics

To develop natural products into clinical drugs, a systematic evaluation of their drug like and pharmacokinetic (ADME) properties is necessary.

1. Analysis of pharmacological parameters

Based on the provided pharmacological parameters, a preliminary evaluation of SSI can be conducted:

• Molecular weight (927.14 Da)Far exceeding the limit of molecular weight<500 in the Lipinski Five Rules. High molecular weight typically means poor drug absorption and permeability, which is a major obstacle in the development of oral medications.
• LogP（2.57）Within the ideal range (-0.4~5.6), it indicates that it has appropriate lipophilicity, which is conducive to membrane permeation.
• TPSA（277.91 Ų）: Far higher than the recommended<140 Å ² for oral medications. High TPSA means that the molecule has a high polarity and is difficult to passively diffuse through the lipid bilayer of the cell membrane, resulting in low oral bioavailability.
• Water solubility (0.0534 mg/mL)Belonging to slightly soluble, with poor water solubility, it can affect its dissolution and absorption in the gastrointestinal tract.
• Blood brain barrier (low)High TPSA and polarity make it difficult to penetrate the blood-brain barrier, which is unfavorable for treating central nervous system diseases, but may be an advantage for treating peripheral diseases such as liver disease and viral infections, reducing central nervous system side effects.
• HERG inhibition (No)This is a positive signal indicating that SSI has a lower risk of causing QT interval prolongation and arrhythmia in the heart.
• Ames test (0.0)A negative result indicates that SSI did not exhibit mutagenicity in the bacterial recovery mutation test and has a low risk of genetic toxicity.

Overall, the challenges of SSI's pharmaceutical potential mainly lie in its high molecular weight, high polarity, and poor water solubility, which may result in low oral absorption and bioavailability. But its good safety (low hERG risk, no mutagenicity) provides a foundation for its development.

2. Pharmacokinetic characteristics

At present, there are few direct research reports on the pharmacokinetics of SSI in vivo, but it can be inferred based on the ADME characteristics of its structural analogues (such as saikosaponin a, d).

• absorb Due to its high molecular weight and polarity, SSI has extremely poor oral absorption. Saponins are often difficult to pass through gastrointestinal epithelial cells. They may be metabolized by gut microbiota, stripped of sugar groups, and converted into secondary glycosides or aglycones, which may be more easily absorbed. Therefore, the systemic exposure of SSI after oral administration may be low, and its efficacy may depend partially or mainly on its intestinal metabolites.
• distribution SSI is mainly distributed in peripheral tissues such as plasma, liver, and kidneys. Due to its high polarity and low BBB permeability, its distribution in brain tissue is extremely rare.
• Metabolism The metabolism of SSI mainly occurs in the gastrointestinal tract and liver. The main metabolic pathways include: ① Deglycosylation Under the action of gut microbiota or hepatic glycosidase, sugar chains are gradually hydrolyzed to produce secondary saponins (such as saikosaponin B series) or aglycones. ② Oxidation The cytochrome P450 enzyme system may undergo oxidative modifications such as hydroxylation of its mother nucleus or sugar chain. ③ Combination reaction Metabolites may combine with glucuronic acid or sulfuric acid to form more water-soluble complexes, which are easier to excrete.
• excretion SSI and its metabolites are mainly excreted into the intestine through bile and excreted with feces. A small amount may be excreted through urine. Due to the presence of hepatic intestinal circulation, its in vivo action time may be prolonged.

Clinical application prospects and prospects

Although saikosaponin I faces challenges in drug development, its unique pharmacological activities, especially broad-spectrum antiviral and anti-inflammatory activities, have opened up broad prospects for its clinical application.

1. Development of antiviral drugs

Given that SSI has inhibitory effects on various viruses such as HSV, HIV, HCMV, and its mechanism of action involves multiple targets, making it less likely to develop drug resistance, it is expected to be developed as a novel antiviral drug. Especially for HSV infection, the commonly used nucleoside analogues in clinical practice, such as acyclovir, have resistance issues. SSI, as a non nucleoside inhibitor, may provide a new treatment option for drug-resistant HSV infections. In addition, the anti HIV activity of SSI is also worthy of further exploration, as its multi-target properties (inhibition of RT and INT, downregulation of co receptors) make it a potential complementary or alternative component to highly effective antiretroviral therapy (HAART).

2. Development of anti-inflammatory and hepatoprotective drugs

The anti-inflammatory and hepatoprotective activities of SSI make it potentially valuable in the treatment of inflammation related diseases such as chronic hepatitis, liver fibrosis, and nephritis. Its low toxicity and multi-target action characteristics make it a safe and effective adjuvant therapy drug. For example, it can be developed into oral formulations (although with low bioavailability, effective ingredients may be produced through gut microbiota metabolism) or injections for long-term management of chronic liver disease.

3. Research on drug delivery systems

In order to overcome the bottleneck of low oral bioavailability of SSI, future research should focus on developing novel drug delivery systems. For example:

• Liposomes or nanoparticles Encapsulating SSI in liposomes or biodegradable polymer nanoparticles can enhance its water solubility, protect it from gastrointestinal degradation, promote its absorption through the lymphatic system, and significantly improve oral bioavailability.
• Phospholipid complex Forming a complex between SSI and phospholipids can improve their lipid solubility and enhance their permeability through biological membranes.
• Prodrug design Chemical modification of hydroxyl groups in SSI molecules, such as introducing phosphate groups, amino acid esters, etc., can improve their water solubility and membrane permeability. The prodrug is released from the body after enzymatic or chemical hydrolysis.

4. Research on Structure Modification and Structure Activity Relationship

The systematic structural modification of SSI and the study of its structure-activity relationship (SAR) are key to discovering derivatives with stronger activity and better drug properties. For example, you can explore:

• Sugar chain modification Change the type, quantity, and connection method of sugars to investigate their effects on activity and solubility.
• Glycoside modification Modify the C-16 acetyl group, C-23 hydroxyl group, C-28 oxygen bridge, etc., and explore their contributions to activity.
• Introduce new functional groups Introducing halogens, nitrogen-containing heterocycles, and other functional groups onto the parent nucleus in order to obtain compounds with higher activity and better selectivity.

Conclusion

Chaihu saponin I, as an important trace triterpenoid saponin component in plants of the Chaihu genus, exhibits enormous pharmacological potential beyond its content due to its unique 13,28-epoxyoleanane skeleton and diverse sugar substitutions. From antiviral, anti-inflammatory to hepatoprotective, its multi-target mechanism of action gives it unique advantages in treating complex diseases. However, its inherent physicochemical properties, such as high molecular weight, high polarity, and low water solubility, result in low oral bioavailability, becoming the main obstacle on its clinical translation path.

Future research needs to focus on improving its drug properties through medicinal chemistry (structural modification, prodrug design) and pharmacology (novel delivery systems) based on a deeper understanding of its mechanism of action and pharmacokinetic characteristics in vivo. Meanwhile, utilizing modern omics technologies such as proteomics and metabolomics, as well as systems biology methods, to comprehensively reveal its functional network and metabolic fate in vivo, will provide scientific guidance for more precise development of SSI and its derivatives. Despite the numerous challenges ahead, saikosaponin I is undoubtedly a highly valuable natural product lead compound, and its application prospects in the fields of antiviral and anti-inflammatory are worth looking forward to. With the continuous deepening of research, this "new star" in ancient Chinese medicine is expected to shine brightly in future clinical treatments.