Product name: Liquidambaric acid
Synonym name: Betulonic acid
Catalogue No.: BP0871
Cas No.: 4481-62-3
Formula: C₃₀H₄₆O₃
Mol Weight: 454.695
Botanical Source: Liquidambar formosana Hance
Physical Description:
Type of Compound: Triterpenoids

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.


The product could be supplied from milligrams to grams
Inquire for bulk scale.

Description:

Betulonic acid has anti-cancer , anti-HIV,hepatoprotective and anti-inflammatory activities, it has antiviral activity against herpes simplex virus, it also suppresses ECHO 6 virus reproduction. Betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents.

References:

Bioorg Med Chem. 2014 Jul 1;22(13):3292-300.    

Synthesis of triterpenoid triazine derivatives from allobetulone and betulonic acid with biological activities.    

The synthetic transformation and modification of natural products with the aim to improve the biological properties is an area of current interest. The triterpenoids betulin and betulinic acid are very abundant in nature and now are commercially available. 

METHODS AND RESULTS:

In our study, starting from betulin and betulinic acid, we obtained allobetulone and Betulonic acid in a few synthetic steps. The ketone function at the A-ring was used as the starting point for the synthesis of a series of 1,2,4-triazine-fused triterpenoids. The alkylation and Liebeskind-Srogl coupling were used for further substitution of 1,2,4-triazines, and the intramolecular hetero Diels-Alder reaction leads to interesting fused thienopyridine derivatives. All new compounds were tested for their cytostatic activities against murine leukemia L1210, human cervix carcinoma HeLa and human lymphoblast CEM tumor cells. 

CONCLUSIONS:

The results show that some triterpenoid triazine Betulonic acid derivatives have a promising cytostatic activity in vitro and could be used as potential leads for the development of new type of anti-cancer agents. Several compounds were also endowed with anti-HCMV activity in the low micromolar range.   

Fitoterapia. 2003 Jul;74(5):489-92.    

Antiviral activity of betulin, betulinic and betulonic acids against some enveloped and non-enveloped viruses.    

METHODS AND RESULTS:

Antiviral properties of betulin, betulinic and Betulonic acids were investigated in cell cultures infected with herpes simplex type I, influenza FPV/Rostock and ECHO 6 viruses. 

CONCLUSIONS:

All studied triterpenes were active against herpes simplex virus. Betulin and especially betulinic acid also suppressed ECHO 6 virus reproduction.    

Bioorg Med Chem. 2009 Jul 15;17(14):5164-9.Efficient synthesis of the first betulonic acid-acetylene hybrids and their hepatoprotective and anti-inflammatory activity.

The Sonogashira reaction can be applied for the preparation of acetylenic derivatives of Betulonic acid where the triterpenoid moiety can serve as either the halo- or the acetylenic component. This reaction opened access to the first derivatives of Betulonic acid containing either the arylethynyl (C[triple bond]C-Ar(Het) or the ethynyl (C[triple bond]CH) moieties. From the fundamental perspective, this work illustrates the possibility of selective Pd-catalyzed cross-coupling at terminal acetylenes in the presence of a terminal alkene. 

METHODS AND RESULTS:

Hepatoprotective and anti-inflammatory properties of selected acetylenic derivatives of Betulonic acid were investigated using the CCl4-induced hepatitis and carrageenan-induced edema models, respectively.

HPLC of Liquidambaric acid

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, play an irreplaceable role in the long history of human struggle against diseases. Triterpenes, as a class of structurally diverse and biologically active natural secondary metabolites, have always been a hot topic in medicinal chemistry and pharmacology research. Among them, Liquidabaric acid, also known as Betulonic acid, is a typical pentacyclic triterpenoid acid that has attracted much attention due to its significant biological activity, especially its enormous potential in anti-inflammatory and antiviral fields in recent years.

Lulutonic acid, CAS number 4481-62-3, is commonly known as 3-oxo-20 (29) - lupen-28-oic acid. Structurally, it belongs to the pentacyclic triterpenoid of the lupine type and is a 3-carbonyl derivative of Betulinic acid. This slight structural difference endows Lulutonic acid with unique physicochemical properties and biological activity spectrum. Early research focused on its anti-tumor activity, but in recent years, with a deeper understanding of signaling pathways related to inflammation and viral infections, the role of lulutonic acid in anti-inflammatory and anti coronavirus effects has gradually been revealed, making it a highly promising natural lead compound.

Inflammation is a defensive response of the body to harmful stimuli, but excessive or sustained inflammatory response is a core link in the pathological process of various chronic diseases (such as rheumatoid arthritis, inflammatory bowel disease, neurodegenerative diseases) and acute infections (such as COVID-19). Viral infections, especially coronavirus infections, often trigger a "cytokine storm", which refers to the excessive release of pro-inflammatory cytokines (such as IL-6, TNF - α) in the body, leading to multi organ damage and even death. Therefore, finding compounds that can effectively inhibit key inflammatory pathways and viral replication has important clinical significance. Lulutonic acid, with its multi-target properties, especially its activity in regulating key inflammatory signaling pathways such as IL-6/STAT3 and NF - κ B, as well as its potential anti coronavirus ability, provides new ideas for the development of novel anti-inflammatory and antiviral drugs.

This article aims to provide a comprehensive and in-depth review of the research status of lulutonic acid, covering its chemical structure, plant sources, extraction process, pharmacological activity, mechanism of action, drug evaluation, and clinical application prospects, in order to provide a systematic reference for further research and development of this natural product.

Chemical structure and physicochemical properties

The chemical structure of lulutonic acid is the basis of its biological activity. Its core skeleton is a pentacyclic triterpenoid of the lupine type, consisting of five fused rings (A, B, C, D, E). Compared with betulinic acid, the most significant structural feature of Lulutonic acid is that the C-3 position of the A ring is a ketone carbonyl group (=O), rather than a hydroxyl group (- OH). In addition, it has an isopropylidene side chain (C-20, C-29) on its E-ring, as well as a carboxyl group at position C-28. Its system names are usually: (1R, 3aS, 5aR, 5bR, 7aR, 9S, 11aR, 11bR, 13aR, 13bR) -9-isopropenyl-3a, 5a, 5b, 8,8,11a-hectamethyl-1-propan-1-en-2-yl-1,2,3,4,5,6,7,7a, 9,10,11,11b, 12,13,13a, 13b-hexahydrocyclopentane-3-a-carboxylic acid.

From the perspective of physical and chemical properties, Lulutonic acid (molecular formula C ∝₀ H ₄₆ O3, molecular weight 454.69 Da) exhibits typical lipophilic characteristics. Its calculated LogP value is as high as 6.1759, indicating that it has strong lipid solubility and is easily soluble in organic solvents such as chloroform, methanol, ethanol, and dimethyl sulfoxide, while its solubility in water is extremely low (about 0.0010 mg/mL). This high lipophilicity has a significant impact on its absorption, distribution, metabolism, and excretion (ADME) processes in organisms. Its topological polar surface area (TPSA) is 54.37 Å ², mainly contributed by one carboxyl group and one ketone group, which is at a moderate level, indicating that it may have a certain degree of cell membrane permeability. It is worth noting that its blood-brain barrier (BBB) penetration is predicted to be "high", which provides the possibility for its application in central nervous system diseases such as neuroinflammation. In addition, preliminary pharmacological evaluation showed that the inhibitory risk of lulutonic acid on hERG potassium channels was low (hERG inhibition: no), and the result in Ames test was negative (0.0), indicating that it does not have significant genetic toxicity, which provides initial assurance for its safety as a candidate drug.

Plant sources and extraction methods

Lulutonic acid is not a rare natural product, it is widely distributed in nature and mainly exists in the Hamamelidaceae family of maple trees（Liquidambar）In plants, this is also the origin of its Chinese name "Lulutong Acid". In addition, it is also in the Betulaceae family, Betulaceae, genus Betulaceae（Betula）Found in various plants.

1. Main plant sources：

   • Maple tree（Liquidambar formosana Hance）The dried and ripe fruit sequence is the traditional Chinese medicine "Lulutong". Lulutong acid is one of the active ingredients with high content in this medicinal herb, and it is also the direct source of its name.
   • Suhexiang tree（Liquidambar orientalis Mill.）Its resin is the traditional Chinese medicine "Suhexiang" and also contains Lulutong acid.
   • White birch（Betula platyphylla Suk.）The bark of birch is a rich source of betulinic acid and coumaric acid.
   • Other plants Like the triangular maple（Acer buergerianum）Mao Guo Ba Dou（Croton tiglium）The compound was also isolated from plants.

2. Extraction and Separation Purification Methods：
   Due to the lipophilicity of lulutonic acid, its extraction is usually carried out using organic solvent extraction method. Common extraction solvents include ethanol, methanol, or chloroform methanol mixed solvents. In order to improve extraction efficiency and purity, modern separation techniques are widely used.

   • Traditional extraction Usually, reflux extraction or percolation methods are used. Soak the dried and crushed plant materials (such as Lulutong fruit or birch bark) in ethanol or methanol and heat them to reflux. The extract is concentrated to obtain a paste.
   • Modern extraction techniques Ultrasonic assisted extraction and microwave-assisted extraction techniques are used to improve extraction efficiency, shorten extraction time, and reduce solvent usage.
   • Separation and purification The crude extract contains a large amount of impurities and requires further separation and purification. Common methods include:
     • Liquid-liquid extraction Using solvents of different polarities (such as petroleum ether, ethyl acetate, n-butanol) for graded extraction of the extract, lulutonic acid is usually enriched in the moderately polar ethyl acetate or chloroform extraction sites.
     • Column chromatography method Silica gel column chromatography is the most commonly used method, typically using petroleum ether ethyl acetate or chloroform methanol gradient elution. For structurally similar analogues, repeated column chromatography may be required.
     • High performance liquid chromatography (HPLC)Preparation type HPLC is an effective method for obtaining high-purity Lulutonic acid (>98%), especially suitable for trace separation and preparation of standard samples.
     • High Speed Counter Current Chromatography (HSCCC)As a liquid-liquid distribution chromatography technique, HSCCC has the advantages of high sample recovery rate and irreversible adsorption when separating triterpenoid acid compounds such as coumaric acid.

Pharmacological activity research

The pharmacological activity research of lulutonic acid has expanded from early anti-tumor to anti-inflammatory, antiviral, neuroprotective and other fields, demonstrating multiple pharmacological effects.

1. anti-inflammatory activity：
   Inflammation is one of the most in-depth areas of research in the field of rosuvastatin. Numerous in vitro and in vivo experiments have confirmed its significant anti-inflammatory effect.

   • Inhibit pro-inflammatory factors In a macrophage model stimulated by lipopolysaccharide (LPS), lulutonic acid can significantly inhibit the production of pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), interleukin-1 β (IL-1 β), and nitric oxide (NO). Its target is directly related to IL-6, TNF, NOS2, etc.
   • Animal model validation In various acute inflammation models (such as carrageenan induced toe swelling and xylene induced ear swelling) and chronic inflammation models (such as collagen induced arthritis), lulutonic acid exhibits dose-dependent anti-inflammatory effects, effectively reducing edema, inhibiting inflammatory cell infiltration, and tissue damage.

2. Antiviral activity：
   In recent years, the antiviral activity of lulutonic acid, especially its anti coronavirus activity, has become a research hotspot.

   • Anti coronavirus Research shows that Lulutong acid has inhibitory effect on many coronaviruses, including SARS-CoV-2 (COVID-19) and its variants. Its mechanism of action may involve inhibiting the entry of viruses into host cells, suppressing the activity of viral proteases (such as 3CLpro), or regulating the inflammatory response of host cells. Its potential as an "anti coronavirus agent" has been preliminarily confirmed.
   • Other viruses In addition, there are also reports indicating that lulutonic acid has a certain inhibitory effect on influenza virus, herpes simplex virus, and other viruses.

3. Antitumor activity：
   As an analog of betulinic acid, lulutonic acid also inherits its anti-tumor activity. Studies have shown that it has cytotoxicity to a variety of cancer cell lines (such as melanoma, lung cancer, breast cancer, liver cancer, etc.), can induce apoptosis and autophagy, and inhibit tumor cell migration and invasion. The mechanism may be related to the regulation of signaling pathways such as STAT3 and NF - κ B.

4. Neuroprotective effect：
   Given its excellent blood-brain barrier penetration, lulutonic acid has also shown protective effects in neurodegenerative disease models. It can inhibit neuroinflammation mediated by microglia, reduce neurotoxicity induced by β - amyloid protein (A β), and alleviate oxidative stress damage by activating antioxidant pathways such as Nrf2.

5. Other activities：
   Lulutonic acid has also been reported to have various biological activities such as antibacterial, antiparasitic (such as Plasmodium and Leishmania parasites), hepatoprotective, and hypoglycemic effects, but its specific mechanism and in vivo effectiveness still need further verification.

Mechanism of action and molecular targets

The pharmacological activity of lulutonic acid is the result of the combined action of multiple targets and pathways. Its core mechanism mainly revolves around the regulation of inflammatory signaling pathways and viral life cycle.

1. Anti inflammatory mechanism：

   • Inhibition of NF - κ B signaling pathway NF - κ B is the core transcription factor of inflammatory response. Lulutonic acid can inhibit the activity of I κ B kinase (IKBKB), prevent the phosphorylation and degradation of I κ B α, thereby blocking the nuclear translocation of NF - κ B (RELA is one of its subunits) and downregulating the expression of downstream target genes such as TNF - α, IL-6, NOS2, PTGS1/COX-1. PTGS1 and PTGS2 (COX-2) are key enzymes involved in prostaglandin synthesis, and their inhibition is a target of classical nonsteroidal anti-inflammatory drugs.
   • Regulating the IL-6/STAT3 signaling pathway IL-6 is a key pro-inflammatory cytokine that activates JAK kinase upon binding to receptors, leading to phosphorylation and activation of transcription factor STAT3. Activated STAT3 enters the nucleus, promoting the transcription of various pro-inflammatory and pro proliferative genes. Lulutonic acid can directly or indirectly inhibit the phosphorylation of STAT3, thereby blocking the signaling pathway and reducing inflammatory response.
   • Inhibit NLRP3 inflammasome CASP1 (Caspase-1) is a key effector molecule of NLRP3 inflammasome activation, responsible for cleaving pro-IL-1 β and pro-IL-18 into mature forms. Research has shown that lulutonic acid may decrease the secretion of IL-1 β and IL-18 by inhibiting the assembly or activity of NLRP3 inflammasomes, reducing the activation of CASP1.
   • Regulating ion channels TRPV1 and TRPA1 are members of the transient receptor potential (TRP) ion channel family, highly expressed in sensory neurons and involved in the transmission of pain and inflammatory signals. Lulutonic acid has been found to antagonize the activity of TRPV1 and TRPA1, which may be another pathway for its analgesic and anti-inflammatory effects.

2. Mechanism of action against coronavirus：

   • Inhibit virus entry The binding of the spike protein (S protein) of coronavirus to the ACE2 receptor on the surface of host cells is the first step of virus invasion. Some studies suggest that lulutonic acid may interfere with the recognition and fusion process between the virus and host cells by binding to S proteins or ACE2 receptors.
   • Inhibition of viral protease The main proteases of coronavirus (3CLpro/Mpro) and papain like protease (PLpro) are crucial in the processing of viral polyprotein. Molecular docking and enzyme activity experiments have shown that lulutonic acid can bind to the active sites of these proteases, inhibit their enzymatic activity, and thus block virus replication.
   • Regulating host immune response As mentioned earlier, coronavirus infection often triggers a "cytokine storm". The strong anti-inflammatory activity of lulutonic acid, especially its inhibition of the IL-6, TNF - α, and NF - κ B pathways, helps alleviate the excessive inflammatory response caused by viral infection, thereby protecting host organs from damage. This may be an important auxiliary mechanism for its antiviral effect.

3. Mechanism of anti-tumor action：
   Lulutonic acid exerts anti-tumor effects through various mechanisms such as inducing apoptosis (activating Caspase family proteins), inducing autophagy, blocking the cell cycle (such as G1/S phase arrest), inhibiting angiogenesis (downregulating VEGF), and reversing epithelial mesenchymal transition (EMT). Among them, inhibition of the STAT3 and NF - κ B pathways also played a key role.

Evaluation of drug properties and pharmacokinetics

Despite the multifaceted pharmacological activities of lulutonic acid, its development as an oral drug still faces significant challenges, mainly focused on pharmacokinetic (PK) properties.

1. Analysis of drug properties parameters：

   • Advantage The molecular weight (454.69 Da) meets the requirement of the Lipinski Five Rules for molecular weight<500. Although the LogP value (6.1759) is high, it is still within an acceptable range. The absence of hERG inhibition and Ames toxicity is an important safety advantage.
   • disadvantage The most prominent issue is its extremely low water solubility (0.0010 mg/mL). This directly leads to extremely low oral bioavailability, severely limiting its absorption and efficacy in the body. A high LogP value also means that its metabolism may be faster and it is prone to accumulate in adipose tissue.

2. Pharmacokinetic characteristics：

   • absorb Poor oral absorption and low bioavailability. Its high lipophilicity makes it difficult to dissolve and absorb in the aqueous environment of the gastrointestinal tract.
   • distribution Due to its high lipophilicity, lulutonic acid is widely distributed in the body, especially easily entering lipid rich tissues such as the liver, adipose tissue, and brain. The high blood-brain barrier penetration predicted by it is a double-edged sword. On the one hand, it is beneficial for treating central nervous system diseases, but on the other hand, it may also bring potential toxicity to the central nervous system.
   • Metabolism The main metabolic pathway may involve the CYP450 enzyme system in the liver, which undergoes oxidation, reduction (such as the reduction of the 3-keto group to a hydroxyl group, producing betulinic acid), and glucuronic acid binding reactions.
   • excretion Mainly excreted through bile and feces, the amount of prototype drug excreted through the kidneys is very small.

3. Strategies for improving drug properties：
   Given its extremely poor water solubility, structural modification or adoption of novel drug delivery systems is key to enhancing the pharmacological properties of lulutonic acid.

   • Prodrug design Derive the carboxyl group at C-28 or the ketone group at C-3 to prepare ester, amide, or phosphate prodrugs for improved water solubility and oral absorption. For example, esters formed with amino acids or sugars.
   • salt formation Forming salts with alkaline amino acids (such as lysine and arginine) or inorganic bases (such as sodium hydroxide) can significantly improve water solubility.
   • nano-formulation By utilizing technologies such as liposomes, polymer nanoparticles, micelles, and nanocrystals, the solubility, stability, and bioavailability of LuLuTong acid can be significantly improved by encapsulating or adsorbing it onto nanocarriers, and targeted delivery can be achieved.
   • Cyclodextrin inclusion complex Forming inclusion complexes with β - cyclodextrin or its derivatives is also a common method for improving water solubility and stability.

Clinical application prospects and prospects

Lulutonic acid, as a natural triterpenoid acid with multiple pharmacological activities, has broad clinical application prospects, but also faces many challenges.

1. Potential application areas：

   • antiinflammatory drug Based on its strong anti-inflammatory activity, especially in inhibiting the IL-6/STAT3 and NF - κ B pathways, lulutonic acid or its derivatives are expected to be developed for the treatment of various chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, psoriasis, etc.
   • antiviral drugs Given its anti coronavirus activity, lulutonic acid is a promising lead compound for anti-SARS-CoV-2. Especially with its dual antiviral and anti-inflammatory effects, it has unique advantages in treating COVID-19 and the "cytokine storm" it triggers. In the future, in-depth research can be conducted on its antiviral mechanism and developed into oral or inhaled formulations.
   • Neuroprotective agent Its excellent blood-brain barrier penetration and neuroprotective effects make it promising for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
   • Antitumor adjuvant drugs Although its direct anti-tumor activity may not be as good as some chemotherapy drugs, its anti-inflammatory and immunomodulatory effects make it a promising adjuvant drug for cancer treatment, used to alleviate the inflammatory response caused by chemotherapy or enhance the efficacy of immunotherapy.

2. Future research directions：

   • In depth mechanism research Although it is known to act on multiple targets, the specific molecular binding mode, fine regulation of downstream signaling networks, and the correlation between different activities still need further clarification. For example, the synergistic mechanism between its anti-inflammatory and antiviral activities.
   • Research on Structural Optimization and Structure Activity Relationship (SAR)Using Lulutonic acid as the parent nucleus, systematically modify its structure to explore the effects of substituents at different sites (such as C-3, C-28, C-20 side chains) on its activity, selectivity, and pharmacokinetic properties, and search for candidate compounds with stronger activity, lower toxicity, and better pharmacokinetic properties.
   • Development of a new drug delivery system Combining modern pharmaceutical technologies (such as nanotechnology) with Lulutonic acid to solve its core problems of poor water solubility and low bioavailability is the key to achieving its clinical translation.
   • Toxicological evaluation of the system Although the Ames test is negative, a comprehensive evaluation of acute and chronic toxicity, reproductive toxicity, neurotoxicity, etc. is still needed to ensure the safety of its use.
   • Preclinical and clinical research After completing sufficient pharmacological, pharmacokinetic, and toxicological evaluations, it should be actively promoted to enter the clinical trial phase to verify its effectiveness and safety in humans.

Conclusion

Lulutong acid, as a natural triterpenoid acid derived from traditional Chinese medicine "Lulutong" and "Baihua", has shown important research value and development potential in multiple fields such as anti-inflammatory, antiviral, and anti-tumor due to its unique lupine structure and multi-target pharmacological activity. Especially its role in regulating key inflammatory pathways such as IL-6/STAT3 and NF - κ B, as well as inhibiting coronaviruses, makes it a potential candidate molecule for addressing current global health challenges such as the COVID-19 pandemic and chronic inflammatory diseases.

However, its extremely low water solubility and oral bioavailability are the biggest obstacles to its transition from laboratory to clinical application. Future research should focus on overcoming this bottleneck through structural modification, prodrug design, or advanced drug delivery systems. Meanwhile, in-depth analysis of its mechanism of action and comprehensive safety evaluation are also essential steps. It can be foreseen that with the continuous deepening of research and technological progress, lulutonic acid and its derivatives are expected to contribute to human health in the near future, becoming a new star originating from the treasure trove of natural products.