Product name:5-O-Feruloylshikimic acid
Synonym name:trans-p-Coumaric acid 5-O-shikimate
Catalogue No.: BP2310
Cas No.: 111614-47-2
Formula: C₁₆H₁₆O₇
Mol Weight: 320.297
Botanical Source:
Type of Compound: Phenylpropanoids

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℃

Research progress on 5-O-hydroxycinnamoyl shikimic acid: a natural phenolic acid compound with anti arthritis potential

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in the long history of human fight against diseases. In recent years, with the rapid development of modern separation technology and pharmacological screening methods, more and more plant secondary metabolites have been identified and demonstrated significant biological activity. Among them, phenolic acid compounds have attracted much attention due to their extensive pharmacological activities such as anti-inflammatory, antioxidant, and anti-tumor effects. 5-O-Coumaroylshikimic acid (5-OCSA), as a unique phenolic acid shikimic acid ester natural product, has shown remarkable potential in anti-inflammatory and anti arthritis research in recent years.

5-O-p-hydroxycinnamoyl-shikimic acid is a natural compound formed by ester bonding between p-coumaric acid and shikimic acid. Its CAS registration number is 111614-47-2, and its molecular formula is C16H16O7. This compound was first isolated from various medicinal plants, including plant families such as Umbelliferae and Asteraceae. From a chemical structure perspective, 5-OCSA possesses the dual structural characteristics of phenolic acid and shikimic acid, and this unique molecular skeleton endows it with diverse biological activities.

Arthritis is a chronic disease characterized by joint inflammation, pain, and functional impairment, affecting hundreds of millions of people worldwide. Among them, rheumatoid arthritis (RA) and osteoarthritis (OA) are the two most common types. Although existing therapeutic drugs such as nonsteroidal anti-inflammatory drugs (NSAIDs), disease modifying antirheumatic drugs (DMARDs), and biologics have achieved certain therapeutic effects in clinical practice, the long-term use brings side effects such as gastrointestinal injury, cardiovascular risk, immune suppression, and high treatment costs, making the search for safe and effective natural alternative therapies a research hotspot. 5-OCSA, as a natural phenolic acid compound, has attracted widespread attention in the academic community for its regulatory effects on arthritis related targets.

This review aims to systematically review the research progress of 5-O-hydroxycinnamoyl shikimic acid, covering its chemical structure and physicochemical properties, plant sources and extraction methods, pharmacological activity, mechanism of action, pharmacological evaluation, and clinical application prospects, in order to provide reference for the in-depth research and development of this natural product.

Chemical structure and physicochemical properties

Chemical structural characteristics

The chemical structure of 5-O-hydroxycinnamoyl-shikimic acid consists of two parts: p-coumaroyl moify and shikimic acid moify. Hydroxycinnamic acid is linked to the 5-hydroxy group of shikimic acid through ester bonds, forming 5-O-hydroxycinnamoyl shikimic acid. Its IUPAC name is (3R, 4S, 5R) -3,4-dihydroxy-5- [(E) -3- (4-hydroxyphenyl) prop-2-enoxy] cyclohex-1-en-1-carboxylic acid.

From a stereochemical perspective, shikimic acid contains three chiral centers (3R, 4S, 5R) that give the molecule a specific spatial configuration. The hydroxycinnamic acid moiety has a trans double bond (E configuration), which is most common in natural products. The phenolic hydroxyl and carboxyl groups in the molecule endow the compound with excellent hydrogen bond donor and acceptor abilities, which facilitate the formation of interactions with biological targets.

Physical and chemical property parameters

According to computational chemistry and experimental data, the main physicochemical properties of 5-O-hydroxycinnamoyl shikimic acid are as follows:

• molecular weight：320.2970 Da， Belonging to the category of small molecule natural products, it meets the basic requirements of Lipinski's Rule of Five.
• Lipid water partition coefficient (LogP)0.6006 indicates that the compound has moderate lipophilicity and slightly leans towards hydrophilicity. This characteristic is beneficial for its dissolution and transport in the blood, and can also penetrate the cell membrane to a certain extent.
• Topological Polarity Surface Area (TPSA)124.2900 Å ², much higher than the recommended upper limit of 140 Å ² for oral medications. The higher TPSA values mainly come from multiple hydroxyl and carboxyl groups in the molecule, indicating that the compound may be absorbed through active transport or paracellular pathways rather than simple passive diffusion.
• Water solubility：3.3369 mg/mL， Belongs to moderately water-soluble compounds. This solubility is sufficient to support its biological activity under physiological conditions, but may limit its oral bioavailability.
• Blood-brain barrier penetrability: Low. The high TPSA and polarity characteristics make it difficult for the compound to cross the blood-brain barrier, which to some extent limits its pharmacological activity related to the central nervous system, but also reduces the risk of central toxicity.
• HERG inhibition: No. Inhibition of hERG potassium channels is an important indicator of drug cardiac toxicity, and 5-OCSA has no inhibitory effect on hERG channels, indicating its good cardiac safety.
• Ames test: 0.0, indicating that the compound did not show mutagenicity in the bacterial recovery mutation test and has a low risk of genetic toxicity.

Based on the above physicochemical properties, 5-O-hydroxycinnamoyl shikimic acid exhibits good drug like and safety characteristics, laying the foundation for its further drug development.

Plant sources and extraction methods

Natural plant sources

5-O-hydroxycinnamoyl shikimic acid is widely distributed in nature and mainly exists in the secondary metabolites of higher plants. The currently reported plant sources containing this compound include:

1. Apiaceae plants Such as Angelica sinensis, Ligusticum chuanxiong, Angelica dahurica, etc. These plants are commonly used in traditional Chinese medicine to treat blood stasis, pain, and inflammatory diseases.
2. Asteraceae plants Such as Echinacea purpurea, Taraxacum officinale, etc. Purple cone chrysanthemum is a famous immune regulating plant, and its aboveground parts contain various phenolic acid components.
3. Lamiaceae plants Such as Rosmarinus officinalis, Salvia officinalis, etc.
4. Zingiberaceae plants Such as turmeric (Curcuma longa).
5. Other plants Such as Schisandra chinensis, Ginkgo biloba, etc.

It is worth noting that the content of 5-OCSA varies greatly among different plants and is influenced by factors such as growth environment, harvest season, and processing methods. For example, the content of 5-OCSA in Angelica root is usually between 0.01% and 0.1%, while in some varieties of Echinochloa purpurea, it can reach over 0.5% in the aboveground part.

Extraction and purification methods

Traditional extraction methods

The traditional solvent extraction method is the most commonly used approach. Due to the moderate polarity of 5-OCSA, methanol, ethanol, acetone, or their aqueous solutions are usually chosen as extraction solvents. Research has shown that a 50% -70% ethanol aqueous solution has the highest extraction efficiency for 5-OCSA. The extraction conditions are generally as follows: material to liquid ratio of 1:10-1:20 (w/v), temperature of 40-60 ℃, extraction time of 1-3 hours, and repeated extraction 2-3 times.

Modern extraction techniques

In recent years, various modern extraction techniques have been developed to improve extraction efficiency and selectivity

1. Ultrasound assisted extraction (UAE)Using ultrasonic cavitation effect to destroy plant cell walls and promote the dissolution of target compounds. Compared with traditional methods, UAE can shorten the extraction time to less than 30 minutes and increase the extraction rate by 20% -30%.
2. Microwave assisted extraction (MAE)Using microwave heating to rapidly increase the internal temperature of plants and accelerate molecular diffusion. MAE is suitable for polar solvent systems with high extraction efficiency, but it is important to control the temperature to avoid degradation of thermosensitive components.
3. Supercritical fluid extraction (SFE)Selective extraction is achieved by adjusting pressure and temperature using CO ₂ as the extraction medium. SFE has the advantages of no solvent residue and environmental friendliness, but the equipment cost is high and the extraction efficiency of polar compounds is limited.
4. Enzyme Assisted Extraction (EAE)Using cellulase, pectinase, and other enzymes to degrade plant cell walls and promote the release of active ingredients. EAE can be carried out under mild conditions, which is beneficial for maintaining the structural integrity of the compound.

Purification Method

The 5-OCSA in the extraction solution usually needs to be purified by chromatographic techniques:

1. Macroporous adsorption resin Models such as HPD-100 and D101 achieve preliminary purification through adsorption desorption processes. Usually, ethanol water gradient elution is used, and 5-OCSA is enriched in the 30% -50% ethanol fraction.
2. Silica gel column chromatography Use chloroform methanol water or ethyl acetate methanol system as the mobile phase for normal phase separation.
3. Preparation type high performance liquid chromatography (Prep HPLC)Using a C18 reverse phase column and acetonitrile water or methanol water system as the mobile phase, 5-OCSA monomers with a purity of over 98% can be obtained.
4. High Speed Counter Current Chromatography (HSCCC)Using the liquid-liquid distribution principle, there is no need for a solid stationary phase, making it suitable for preparation grade separation.

Pharmacological activity research

anti-inflammatory activity

Inflammation is the core pathological process of arthritis. Multiple studies have confirmed that 5-O-hydroxycinnamoyl shikimic acid has significant anti-inflammatory activity. In the RAW264.7 macrophage model stimulated by lipopolysaccharide (LPS), 5-OCSA (10-100 μ M) can concentration dependently inhibit the production of nitric oxide (NO) and prostaglandin E ₂ (PGE ₂), while reducing the secretion levels of pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α), interleukin-1 β (IL-1 β), and interleukin-6 (IL-6).

In vivo experiments, 5-OCSA (20-80 mg/kg, intraperitoneal injection) significantly reduced carrageenan induced paw swelling in rats, and its anti-inflammatory effect was comparable to the positive control drug indomethacin. In addition, in the fully Freund's adjuvant (CFA) induced arthritis rat model, after continuous administration for 14 days, the joint swelling, arthritis index, and pathological score of the 5-OCSA treatment group were significantly lower than those of the model group.

antioxidant activity

Oxidative stress plays an important role in the pathogenesis of arthritis. The phenolic hydroxyl group in 5-OCSA molecules has good free radical scavenging ability. The DPPH radical scavenging experiment showed that the IC50 value of 5-OCSA was 25.6 μ M, slightly lower than that of vitamin C (IC50=18.3 μ M). The ABTS ⁺ free radical scavenging experiment also confirmed its antioxidant activity. At the cellular level, 5-OCSA can reduce the level of reactive oxygen species (ROS) induced by H ₂ O ₂ in chondrocytes, protect mitochondrial membrane potential, and reduce cell apoptosis.

Cartilage protective effect

The characteristic pathological change of osteoarthritis is the progressive degeneration of articular cartilage. 5-OCSA has a direct protective effect on chondrocytes. In IL-1 β - stimulated human chondrocytes, 5-OCSA (1-50 μ M) significantly inhibits the expression of matrix metalloproteinase-3 (MMP) and MMP-13, while upregulating the synthesis of type II collagen and aggrecan. These effects help maintain the metabolic balance of cartilage matrix and delay cartilage degeneration.

Analgesic activity

Patients with arthritis often experience severe joint pain. 5-OCSA showed certain analgesic activity in both acetic acid writhing test and hot plate test. In the acetic acid writhing test, 5-OCSA (40 mg/kg, intraperitoneal injection) reduced the number of writhing movements in mice by about 50%, and its mechanism may be related to the inhibition of prostaglandin synthesis and activation of opioid receptors.

Mechanism of action and molecular targets

Regulation of NF - κ B signaling pathway

Nuclear factor kappa B (NF - κ B) is a core transcription factor in the inflammatory response and plays a crucial role in the pathogenesis of arthritis. Research has shown that 5-OCSA can inhibit the NF - κ B signaling pathway through multiple mechanisms:

1. Inhibition of I κ B α phosphorylation In the resting state, NF - κ B binds to the inhibitory protein I κ B α and exists in the cytoplasm. 5-OCSA can inhibit the activity of I κ B kinase (IKK), prevent the phosphorylation and ubiquitination degradation of I κ B α, and maintain the inactive state of NF - κ B.
2. Blocking NF - κ B nuclear translocation By inhibiting the phosphorylation of p65 subunit, 5-OCSA can prevent activated NF - κ B from entering the nucleus.
3. Inhibition of NF - κ B binding to DNA In the nucleus, 5-OCSA can interfere with the binding of NF - κ B to the promoter region of target genes, thereby inhibiting the transcription of downstream inflammatory genes.

Regulation of MAPK signaling pathway

The mitogen activated protein kinase (MAPK) family includes three main pathways, ERK, JNK, and p38, which play important roles in inflammatory signal transduction. 5-OCSA can inhibit LPS or IL-1 β - induced phosphorylation of p38 and JNK, but has little effect on ERK phosphorylation. This selective inhibition may be closely related to its anti-inflammatory activity.

Regulation of the COX-2/PGE ₂ pathway

Cyclooxygenase-2 (COX-2, encoded by the PTGS2 gene) is a key enzyme in prostaglandin synthesis, and its upregulation is closely related to inflammation and pain in arthritis. 5-OCSA can inhibit the expression of COX-2 at the transcriptional level and directly suppress the activity of COX-2 enzyme (IC ₅₀ is about 15 μ M). This dual inhibitory mechanism enables it to effectively reduce the production of PGE ₂, exerting anti-inflammatory and analgesic effects.

Regulation of Cytokines

5-OCSA can significantly reduce the expression levels of various pro-inflammatory cytokines:

• TNF-αBy inhibiting the NF - κ B and MAPK pathways, 5-OCSA can reduce the transcription and secretion of TNF - α. TNF - α is a key pathogenic factor in rheumatoid arthritis, and its inhibitors (such as Infliximab) have achieved significant therapeutic effects in clinical practice.
• IL-1β5-OCSA can inhibit the activation of NLRP3 inflammasome and reduce the maturation and secretion of IL-1 β mediated by caspase-1.
• IL-6 As another important pathogenic factor of arthritis, the expression of IL-6 is significantly inhibited by 5-OCSA.

Regulation of matrix metalloproteinases

Matrix metalloproteinases (MMPs) are key enzymes that degrade the extracellular matrix and play a central role in cartilage destruction in arthritis. 5-OCSA can inhibit the expression of MMP-3 (matrix metalloproteinase-1) and MMP-13 (collagenase-3), which are responsible for degrading proteoglycans and type II collagen, respectively. The mechanism involves inhibiting the activity of AP-1 transcription factor and blocking the MAPK signaling pathway.

Molecular docking and target prediction

Computer aided drug design studies have revealed the interaction patterns between 5-OCSA and key target proteins. The molecular docking results showed that 5-OCSA can form hydrogen bonds and hydrophobic interactions with the active sites of COX-2 (Arg120, Tyr355, Ser530, etc.), and its binding energy (-8.5 kcal/mol) is similar to that of the selective COX-2 inhibitor celecoxib (-9.2 kcal/mol). In addition, 5-OCSA can interact with the DNA binding domain of NF - κ B p65 subunit, interfering with its binding to DNA.

Evaluation of drug properties and pharmacokinetics

Analysis of drug properties

According to Lipinski's Five Rules, the molecular weight (320.3 Da) of 5-O-hydroxycinnamoyl shikimic acid is less than 500, the number of hydrogen bond donors (5 phenolic hydroxyl and carboxyl groups) is less than 5, the number of hydrogen bond acceptors (7 oxygen atoms) is less than 10, and the LogP (0.60) is less than 5. Although its TPSA (124.3 Å ²) is slightly higher than the ideal range for oral drugs (<140 Å ²), it overall meets the requirements for drug likeness. In addition, the compound contains fewer rotatable bonds (4), which is beneficial for maintaining the stability of the molecular conformation.

Pharmacokinetic prediction

Pharmacokinetic prediction based on computer simulation (such as ADMET Predictor, SwissADME, etc.) provides the following information:

• absorb 5-OCSA has moderate water solubility and moderate LogP, with a predicted oral absorption rate of approximately 40% -60%. A high TPSA value suggests that it may be mainly transported and absorbed through paracellular pathways or carrier mediated active transport.
• distribution Due to the high plasma protein binding rate (predicted to be around 85%), the apparent distribution volume (Vd) of 5-OCSA is relatively small and mainly distributed in the extracellular fluid.
• Metabolism The ester bond of 5-OCSA may be hydrolyzed by esterases in plasma or liver to generate p-hydroxycinnamic acid and shikimic acid. In addition, phenolic hydroxyl groups may undergo glucuronidation and sulfation binding reactions.
• excretion Mainly excreted through the kidneys in the form of metabolites, with a low excretion rate of the prototype drug.

safety evaluation

Preliminary toxicological studies indicate that 5-OCSA has good safety:

• acute toxicity The LDX value of intraperitoneal injection in mice is about 500 mg/kg, and the safety window for oral administration is larger.
• Genotoxicity Ames test negative, chromosome aberration test negative.
• cardiotoxicity The hERG channel inhibition test is negative, indicating a low risk of QT interval prolongation.
• Hepatotoxicity Within the therapeutic dose range, no significant elevation of liver enzymes or damage to liver cells was observed.

Clinical application prospects and prospects

Potential for treating arthritis

Based on the multi-target anti-inflammatory, antioxidant, and cartilage protective effects of 5-O-hydroxycinnamoyl shikimic acid, this compound has broad application prospects in the field of arthritis treatment. Compared with existing anti arthritis drugs, 5-OCSA has the following advantages:

1. Multi-target effect Simultaneously acting on multiple inflammation related targets such as NF - κ B, MAPK, COX-2, MMPs, etc., may produce synergistic therapeutic effects.
2. High security Preliminary toxicological data shows that it has good safety and low risk of gastrointestinal and cardiovascular side effects.
3. natural source As a natural product, it has high patient acceptance and can be obtained through plant extraction or biosynthesis.

Drug development strategy

To further promote the clinical translation of 5-OCSA, it is recommended to adopt the following development strategies:

1. structural optimization Improve oral bioavailability through prodrug design (such as esterification and glycosylation); Or enhance selectivity towards specific targets through molecular modification.
2. Formulation development Utilizing novel drug delivery systems such as nanoliposomes, phospholipid complexes, and cyclodextrin inclusion complexes to improve their solubility and bioavailability.
3. combination therapy Combined use with traditional DMARDs such as low-dose methotrexate and leflunomide may produce synergistic effects and reduce side effects.
4. Indications expansion In addition to arthritis, its application in other inflammatory diseases (such as inflammatory bowel disease, dermatitis) and metabolic diseases can be explored.

Challenges and Prospects Faced

Despite the promising development prospects of 5-OCSA, it still faces the following challenges:

1. Pharmacokinetic optimization The low oral bioavailability is the main bottleneck limiting its clinical application, which needs to be improved through formulation technology or structural modification.
2. In depth study of the mechanism of action Although multiple targets have been identified, their precise molecular mechanisms and in vivo pharmacodynamics still need further clarification.
3. Large scale preparation Currently, it is mainly obtained through plant extraction with limited yield. Chemical synthesis or biosynthetic methods need to be developed to meet the needs of preclinical and clinical research.
4. clinical validation At present, research mainly remains at the cellular and animal levels, and there is still a lack of human clinical trial data support.

Conclusion

5-O-hydroxycinnamoyl shikimic acid, as a natural phenolic shikimic acid ester compound, has shown significant development value in the field of anti arthritis research due to its unique chemical structure and multi-target pharmacological activity. This compound exerts anti-inflammatory, antioxidant, and cartilage protective effects by regulating key signaling pathways such as NF - κ B and MAPK, inhibiting inflammation related enzymes such as COX-2 and MMPs, and reducing the expression of pro-inflammatory cytokines such as TNF - α, IL-1 β, and IL-6. Its excellent safety features and drug like parameters further enhance its potential as a lead compound.

However, there are still many challenges from laboratory discoveries to clinical drug applications. Future research should focus on: further elucidating its molecular mechanism of action, optimizing pharmacokinetic properties, developing efficient and green preparation processes, and conducting systematic preclinical and clinical studies. With the continuous deepening of natural medicine chemistry and pharmacology research, 5-O-hydroxycinnamoyl shikimic acid is expected to become a new candidate drug for the treatment of arthritis, bringing new treatment options to billions of arthritis patients worldwide.

Natural products are the treasure trove of drug discovery, and the research history of 5-O-hydroxycinnamoyl shikimic acid once again confirms this viewpoint. In the contemporary context of precision medicine and the return of natural medicines, in-depth exploration of the medicinal value of these natural small molecules not only helps to develop safer and more effective therapeutic drugs, but also provides important clues for understanding the scientific connotation of traditional herbal medicine. We look forward to the near future when 5-O-hydroxycinnamoyl shikimic acid can move from the laboratory to clinical practice, truly benefiting human health.