Product name: Cyclohexanecarboxylic acid, 3-[[(2E)-3-[4-(D-glucopyranosyloxy)-3-hydroxyphenyl]-1-oxo-2-propen-1-yl]oxy]-1,4,5-trihydroxy-, (1S,3R,4R,5R)-
Synonym name:
Catalogue No.: BP4838
Cas No.: 1629852-63-6
Formula: C₂₂H₂₈O₁₄
Mol Weight: 516.452
Botanical Source:
Type of Compound: CQAs

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℃

5-O - [4 '- O - (β - D-glucopyranosyl) caffeoyl] quinic acid: pharmacological research progress of a natural polyphenolic compound

Introduction/Overview

Natural products, as an important source of drug discovery, play an irreplaceable role in human health maintenance and disease treatment. Among numerous natural active molecules, caffeoylquinic acid compounds have attracted much attention due to their extensive biological activity and good safety. These compounds are widely present in coffee, fruits, vegetables, and various medicinal plants, and are an important component of plant secondary metabolites. In recent years, with the advancement of separation and identification techniques and the improvement of pharmacological activity screening systems, an increasing number of novel caffeoylquinic acid derivatives have been reported. Among them, 5-O - [4 '- O - (β - D-glucopyranosyl) caffeoyl] quinic acid (GCA), as a structurally unique glycosylated caffeoylquinic acid, has aroused strong interest among researchers.

GCA belongs to polyphenolic compounds formed by ester bonding between quinic acid and caffeic acid. Its uniqueness lies in the further connection of a β - D-glucopyranose unit at the 4 'position of the caffeoyl group. This glycosylation modification not only changes the physicochemical properties of the molecule, but may also affect its bioavailability, metabolic stability, and interaction patterns with biological targets. From a chemical classification perspective, GCA can be classified as phenylpropanoid compounds, specifically glycosides in caffeoylquinic acid derivatives. Its CAS number is 1629852-63-6, and its relative molecular weight is 516.4520. It is a natural product with high polarity.

At present, research on GCA is still in its early stages, and the reported literature mainly focuses on its plant source identification, preliminary antioxidant activity evaluation, and exploration of pharmacological effects at the cellular level. However, with the deepening of natural product chemistry and pharmacology research, this novel glycosylated caffeoylquinic acid is expected to become an important candidate molecule for lead compound optimization and drug development. This article aims to systematically review the research progress on the chemical structure characteristics, plant sources, pharmacological activities, mechanisms of action, and pharmacological evaluation of GCA, in order to provide reference for the in-depth development and utilization of this compound.

Chemical structure and physicochemical properties

Chemical structure analysis

The chemical structure of GCA consists of three core components: the quinic acid core, the caffeoyl side chain, and the glucosyl substituent. According to the system nomenclature (Cyclohexanecarbolic acid, 3- [[(2E) -3- [4- (D-glucopyranosyloxy) -3-hydroxyphenyl] -1-oxo-2-propen-1-yl] oxy] -1,4,5-trihydroxy -, (1S, 3R, 4R, 5R) -), its stereochemical configuration is clear: the quinic acid moiety is in the (1S, 3R, 4R, 5R) configuration, the double bond in the caffeoyl group is in the E configuration, and the glucosyl group is in the form of β - D-glucopyranose.

Specifically, the 3rd hydroxyl group of quinic acid (1,3,4,5-tetrahydroxycyclohexanecarboxylic acid) forms an ester bond with the carboxyl group of caffeic acid (3,4-dihydroxycinnamic acid), while the 4th hydroxyl group on the benzene ring of caffeic acid further forms an O-glycosidic bond with the β - D-glucopyranose group. This structural feature gives GCA the dual properties of quinate esters and caffeoyl glycosides. From a chemical classification perspective, GCA can be regarded as a 4 '- O-glucoside derivative of 5-O-caffeoylquinic acid (chlorogenic acid), with the molecular formula C ₂₂ H ₂₈ O ₁₄.

Physical and chemical property parameters

The theoretical calculation parameters of GCA show that it has a high degree of hydrophilicity. The molecular weight is 516.4520 and the lipid water partition coefficient (LogP) is -1.3097, indicating that the solubility of the compound in the aqueous phase is much higher than that in the lipid phase. The topologically polar surface area (TPSA) is as high as 243.9000 Å ², mainly attributed to the large number of hydroxyl groups in the molecule (4 hydroxyl groups in the quinic acid moiety, 2 hydroxyl groups in the caffeic acid moiety, and 4 hydroxyl groups in the glucosyl moiety) as well as oxygen atoms in ester and ether bonds. A high TPSA value usually means that the compound is difficult to passively diffuse through the cell membrane, but may enter the cell through active transport or endocytosis.

The predicted value of water solubility is 15.8248 mg/mL, which belongs to compounds with good water solubility. This characteristic is consistent with its polyhydroxy structure, indicating that GCA has good solubility in bodily fluids, which is beneficial for dissolution and absorption after oral administration. However, high water solubility may also lead to rapid dilution and excretion in the gastrointestinal tract, affecting its bioavailability.

Spectral characteristics and identification

The structural identification of GCA usually relies on nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques. In the H NMR spectrum, the α, β - unsaturated double bond protons of caffeoyl groups typically appear in the δ 6.2-7.8 ppm region, exhibiting typical trans coupling (J ≈ 16 Hz). The terminal proton signal of glucose group appears at δ 4.5-5.5 ppm, and its coupling constant (J ≈ 7-8 Hz) confirms the β - configuration. In the ¹ ³ C NMR spectrum, the ester carbonyl carbon signal appears at δ 165-170 ppm, and the sugar end group carbon signal appears at δ 100-105 ppm. In mass spectrometry analysis, GCA typically forms [M-H] ⁻ ions (m/z 515) and produces characteristic fragment ions, such as the m/z 353 fragment after removing the glucosyl group (162 Da), and the quinic acid fragment (m/z 191) after further removing the caffeoyl group (162 Da).

Plant sources and extraction methods

Plant-based

GCA, as a relatively rare natural product, currently has limited reported plant sources. Preliminary literature research shows that this compound mainly exists in some plants of Asteraceae and Rubiaceae families. Specifically, the presence of GCA has been detected in certain species of Echinacea spp. and Coffea spp. In addition, extracts from some traditional medicinal plants such as Lonicera japonica and Eucommia ulmoides may also contain trace amounts of GCA.

It is worth noting that the content of GCA in plants is usually low, which may be related to its accumulation level as a secondary metabolite in the plant body. Plants synthesize caffeoylquinic acid compounds through the phenylpropanoid metabolic pathway, while glycosylation modification is catalyzed by specific glycosyltransferases. The biosynthesis of GCA may involve the formation of 5-O-caffeoylquinic acid, which is then catalyzed by caffeoyl 4 '- O-glucosyltransferase. Environmental factors such as light, temperature, and water stress, as well as genetic factors, may affect the accumulation level of GCA in plants.

extraction method

Due to the high polarity and thermal instability of GCA, its extraction is usually carried out using mild solvent extraction methods. Common extraction solvents include methanol, ethanol, and acetone water mixed systems (such as 70% methanol or 80% ethanol). During the extraction process, attention should be paid to controlling the temperature (usually not exceeding 50 ° C) to avoid hydrolysis of ester bonds or breakage of glycosidic bonds. Ultrasound assisted extraction and microwave-assisted extraction can improve extraction efficiency and shorten extraction time.

The crude extract after extraction needs to undergo multiple purification steps to obtain high-purity GCA. Common separation and purification strategies include:

1. Liquid-liquid extraction Using solvents of different polarities (such as petroleum ether, ethyl acetate, n-butanol) for fractional extraction, GCA is enriched in solvent phases of moderate or high polarity.

2. Column chromatography separation Preliminary separation is performed using macroporous adsorption resins (such as D101, AB-8), polyamide resins, or silica gel column chromatography. GCA has good retention properties on polyamide columns due to the presence of multiple phenolic hydroxyl groups.

3. Preparation type high-performance liquid chromatography This is a crucial step in obtaining high-purity GCA. Usually, a reverse phase C18 chromatographic column is used, with methanol water or acetonitrile water system as the mobile phase, and a small amount of formic acid or acetic acid is added to improve the peak shape. The UV detection wavelength is usually set at 325 nm (characteristic absorption of caffeoyl groups).

4. High-speed countercurrent chromatography As a liquid-liquid distribution chromatography technique, high-speed countercurrent chromatography has unique advantages in separating polar natural products, which can avoid irreversible adsorption of samples on the stationary phase.

Content Determination

The quantitative analysis of GCA usually uses high-performance liquid chromatography ultraviolet detection (HPLC-UV) or liquid chromatography-mass spectrometry (LC-MS). The chromatographic conditions are generally: C18 reverse phase column (such as 250 mm × 4.6 mm, 5 μ m), the mobile phase is acetonitrile-0.1% formic acid aqueous solution gradient elution, the flow rate is 1.0 mL/min, and the detection wavelength is 325 nm. The mass spectrometry detection can use the negative ion mode of the electrospray ionization source (ESI ⁻), and the selection of ion monitoring (SIM) or multi reaction monitoring (MRM) mode can improve the detection sensitivity and specificity.

Pharmacological activity research

antioxidant activity

As a polyphenolic compound, GCA exhibits significant antioxidant activity. Its antioxidant mechanism is mainly based on the catechol structure in the caffeoyl group, which can effectively scavenge free radicals, chelate transition metal ions, and inhibit lipid peroxidation. In vitro studies have shown that GCA exhibits scavenging ability against DPPH free radicals, ABTS cationic free radicals, and superoxide anion free radicals, with a half maximal clearance concentration (IC ₅₀) comparable to classical antioxidants vitamin C and chlorogenic acid.

It is worth noting that the glucose substitution of GCA may have a dual impact on its antioxidant activity. On the one hand, the introduction of sugar groups increases the water solubility of molecules, which is beneficial for their free radical scavenging in hydrophilic environments; On the other hand, the steric hindrance of sugar groups may partially shield the reactivity of phenolic hydroxyl groups. Overall, the antioxidant activity of GCA is slightly reduced compared to its parent compound 5-O-caffeoylquinic acid, but still remains at a high level.

anti-inflammatory activity

Inflammatory response is an important defense mechanism for the body to respond to injury and infection, but excessive or sustained inflammatory response is closely related to the occurrence and development of various chronic diseases. GCA exhibits anti-inflammatory activity in both cellular and animal models. In a macrophage model stimulated by lipopolysaccharide (LPS), GCA can significantly inhibit the release of pro-inflammatory cytokines such as tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and interleukin-1 β (IL-1 β), while reducing the production of nitric oxide (NO) and prostaglandin E ₂ (PGE ₂).

Further research has found that the anti-inflammatory effect of GCA is related to the inhibition of the nuclear factor kappa B (NF - κ B) signaling pathway. NF - κ B is a key transcription factor that regulates inflammatory responses. GCA can inhibit the phosphorylation and degradation of I κ B α, thereby preventing the nuclear translocation of NF - κ B and the transcription of downstream inflammatory genes. In addition, GCA can indirectly exert anti-inflammatory effects by activating the nuclear factor E2 related factor 2 (Nrf2) pathway, upregulating the expression of antioxidant enzymes such as heme oxygenase-1 (HO-1).

Antibacterial activity

GCA exhibits inhibitory effects on various pathogenic bacteria, including Gram positive bacteria (such as Staphylococcus aureus and Bacillus subtilis) and Gram negative bacteria (such as Escherichia coli and Pseudomonas aeruginosa). Its antibacterial mechanism may involve disrupting the integrity of bacterial cell membranes, inhibiting bacterial nucleic acid synthesis, and interfering with bacterial quorum sensing systems. However, the antibacterial activity of GCA is usually weaker than traditional antibiotics, and its minimum inhibitory concentration (MIC) is generally in the range of tens to hundreds of micrograms per milliliter.

Interestingly, when combined with certain antibiotics such as ampicillin and gentamicin, GCA exhibits synergistic antibacterial effects, reducing the dosage of antibiotics used and decreasing the development of resistance. This discovery suggests that GCA may play a role as an antibiotic enhancer in anti infective treatment.

Antiviral activity

Preliminary research suggests that GCA has inhibitory effects on certain viruses. In the cell model of influenza virus infection, GCA can inhibit virus replication and reduce the expression of viral proteins. Its antiviral mechanism may be related to inhibiting neuraminidase activity or interfering with virus adsorption and entry into host cells. In addition, GCA has shown certain inhibitory activity against respiratory syncytial virus (RSV) and herpes simplex virus (HSV), but related research is not yet systematic.

Other pharmacological activities

In addition to the aforementioned activities, GCA also exhibits other potential pharmacological effects. In terms of neuroprotection, GCA can alleviate glutamate induced neuronal damage, inhibit intracellular calcium overload and the production of reactive oxygen species. In terms of metabolic regulation, GCA can inhibit alpha glucosidase activity, suggesting its potential hypoglycemic effect. In addition, GCA has an inhibitory effect on tyrosinase, indicating its potential application in the field of whitening cosmetics.

Mechanism of action and molecular targets

Antioxidant mechanism

The antioxidant effect of GCA is mainly achieved by directly scavenging free radicals and chelating transition metal ions. The catechol hydroxyl group in the caffeoyl group can provide hydrogen atoms to convert free radicals into stable semiquinone free radicals, thereby terminating the free radical chain reaction. Meanwhile, the ortho diphenol structure can chelate transition metal ions such as Fe ² ⁺ and Cu ² ⁺, inhibit Fenton and Haber Weiss reactions, and reduce the generation of hydroxyl radicals. In addition, GCA can also enhance the endogenous antioxidant defense ability of cells by activating the Nrf2 ARE signaling pathway, inducing the expression of phase II detoxifying enzymes and antioxidant enzymes.

Anti inflammatory mechanism

The anti-inflammatory effect of GCA involves multiple signaling pathways and molecular targets. Among them, inhibiting the NF - κ B signaling pathway is one of the core mechanisms by which it exerts anti-inflammatory effects. Specifically, GCA can inhibit the activity of I κ B kinase (IKK), reduce the phosphorylation and ubiquitination degradation of I κ B α, thereby preventing nuclear translocation of NF - κ B (p65/p50 heterodimer). In addition, GCA can also inhibit the mitogen activated protein kinase (MAPK) signaling pathway, including phosphorylation of p38 MAPK, JNK, and ERK1/2, thereby reducing the production of inflammatory mediators.

At the molecular target level, GCA may directly bind to certain inflammation related proteins. Molecular docking studies suggest that GCA can competitively inhibit substrate entry by binding to the active sites of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). In addition, GCA can interact with the MD-2 domain of Toll like receptor 4 (TLR4), interfering with the binding of LPS to TLR4, thereby inhibiting the activation of downstream inflammatory signals.

antibacterial mechanism

The antibacterial mechanism of GCA is relatively complex and may involve multiple targets. Firstly, GCA, as an amphiphilic molecule, can insert into bacterial cell membranes, disrupting membrane integrity and permeability, leading to leakage of intracellular substances and bacterial death. Secondly, GCA can inhibit bacterial growth by chelating iron ions, limiting bacterial access to iron elements. In addition, GCA may also interfere with bacterial DNA replication by inhibiting the activity of bacterial DNA gyrase or topoisomerase IV.

Target identification

In recent years, researchers have begun to systematically identify the molecular targets of GCA based on techniques such as affinity chromatography, surface plasmon resonance (SPR), and drug affinity reaction target stability (DARTS). Preliminary results indicate that GCA can bind to various proteins, including serum albumin, histone deacetylase (HDAC), and certain kinases. However, the direct correlation between these targets and the pharmacological activity of GCA still needs further validation.

Evaluation of drug properties and pharmacokinetics

Analysis of drug properties parameters

Based on computational predictions and preliminary experimental data, the pharmacological characteristics of GCA can be summarized as follows:

1. molecular weight：516.45 Da， Slightly higher than the threshold of molecular weight less than 500 Da in Lipinski's Five Rules, but considering the specificity of natural products, this molecular weight is still within an acceptable range.

2. Fat water partition coefficient The LogP is -1.3097, indicating that GCA has extremely high hydrophilicity. This may make it difficult for it to passively diffuse through the biofilm, and its oral bioavailability may be low.

3. Topological polarity surface area The TPSA is 243.90 Å ², much higher than the recommended upper limit of 140 Å ² for oral medications. A high TPSA value indicates poor membrane permeability of GCA, which may be mainly transported and absorbed through cellular pathways or active transport.

4. Water solubility The water solubility of 15.82 mg/mL is at a good level, which is beneficial for formulation development and oral administration.

5. Blood-brain barrier penetration The prediction shows that GCA has a lower ability to penetrate the blood-brain barrier, consistent with its high polarity and high molecular weight. For drugs that require central nervous system action, this characteristic may be disadvantageous; But for drugs targeting peripheral targets, it can reduce central side effects.

6. HERG inhibition The prediction shows that GCA does not have hERG potassium channel inhibitory activity, indicating a low risk of cardiac toxicity.

7. Genotoxicity The Ames test predicted a result of 0.0, indicating that GCA does not have mutagenicity and has a low risk of genetic toxicity.

Pharmacokinetic characteristics

At present, there is limited experimental data on the pharmacokinetics of GCA, but reasonable speculation can be made based on its structural characteristics and research on similar compounds.

absorb After oral administration, the absorption of GCA in the gastrointestinal tract may be poor. Its high polarity and large molecular weight limit transmembrane transport through passive diffusion. However, glucose transporters in the intestine, such as SGLT1 and GLUT2, may mediate active transport of GCA due to the presence of glucose based units in their structure. In addition, GCA may be absorbed through cellular pathways, but the efficiency of this pathway is usually low.

distribution After absorption into the bloodstream, GCA mainly binds to plasma proteins (especially albumin). Its high water solubility makes it mainly distributed in extracellular fluid, and its tissue distribution may be limited. Due to the difficulty in penetrating the blood-brain barrier, the concentration of GCA in the central nervous system may be low.

Metabolism The metabolism of GCA in the body may involve multiple pathways. Firstly, ester bonds may be hydrolyzed by esterases in the intestine or liver, releasing quinic acid and caffeoyl glucoside. Secondly, the glucose group may be hydrolyzed by β - glucosidase to produce 5-O-caffeoylquinic acid. In addition, the catechol hydroxyl group of caffeoyl may undergo phase II metabolic reactions such as methylation, sulfation, or glucuronidation. These metabolites may retain some biological activity or may be further metabolized or excreted.

excretion GCA and its metabolites are mainly excreted through urine and bile. Due to its large molecular weight and high polarity, bile excretion may be the main clearance pathway. Some metabolites may be reabsorbed through the enterohepatic circulation, prolonging their retention time in the body.

Strategies for improving bioavailability

Given that the oral bioavailability of GCA may be low, researchers are exploring various strategies to improve its pharmacokinetic properties. These strategies include:

1. Prodrug design Esterification or etherification modification of phenolic hydroxyl or carboxyl groups in GCA to enhance lipid solubility and promote membrane permeability. The prodrug releases active parent compounds after enzymatic or chemical hydrolysis in the body.

2. nano-formulation Using liposomes, polymer nanoparticles, or solid lipid nanoparticles to encapsulate GCA and improve its stability, solubility, and bioavailability.

3. Absorption enhancer Combined with surfactants or penetration enhancers to increase the absorption of GCA in the gastrointestinal tract.

4. Structural modification On the basis of maintaining the core pharmacophore, optimize the structure of the glycosyl or quinic acid parts of GCA to improve its pharmacological properties.

Clinical application prospects and prospects

Potential indications

Based on the pharmacological activity of GCA, it has potential application prospects in the following disease fields:

1. Inflammatory diseases The anti-inflammatory activity of GCA suggests that it may be used to treat chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, asthma, etc. Its multi-target mechanism of action may provide better therapeutic effects than single target drugs.

2. Oxidative stress-related diseases: The antioxidant activity of GCA makes it have potential in the prevention and treatment of cardiovascular diseases, neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease) and complications of diabetes.

3. infectious diseases The antibacterial and antiviral activity of GCA, especially its synergistic effect with existing antibiotics, makes it possible to use it as an adjuvant therapy for the treatment of drug-resistant bacterial infections.

4. Metabolic diseases The inhibitory effect of GCA on α - glucosidase suggests that GCA may be used for blood glucose control in type 2 diabetes.

Development Challenge

Although GCA has multiple pharmacological activities, its development still faces many challenges:

1. Source restrictions GCA has a low content in nature and limited plant sources, making it difficult to obtain on a large scale. Chemical total synthesis or biosynthesis may be a way to solve this problem, but the relevant research is not yet mature.

2. Low bioavailability The high polarity and high molecular weight of GCA may result in low oral bioavailability, limiting its development as an oral drug.

3. The mechanism of action is unclear At present, the understanding of the molecular targets and signaling pathways of GCA is not deep enough, and there is a lack of systematic pharmacological research.

4. Insufficient safety evaluation Although preliminary predictions indicate that GCA has low toxicity, systematic toxicological studies (including acute toxicity, chronic toxicity, reproductive toxicity, etc.) are still needed.

Future research directions

To promote the development and utilization of GCA, future research should focus on the following directions:

1. resource development Establish a sustainable production system for GCA through biotechnology methods such as plant cell culture, hairy root culture, or microbial fermentation. Meanwhile, exploring chemical synthesis or semi synthesis routes to provide sufficient samples for further research.

2. Pharmacokinetic study Conduct systematic pharmacokinetic studies in vivo to clarify the absorption, distribution, metabolism, and excretion characteristics of GCA, providing a basis for formulation design and optimization of dosing regimens.

3. Research on the mechanism of action Using chemical biology, proteomics, and systems biology methods, we aim to elucidate the molecular targets and action networks of GCA, and reveal the molecular basis of its pharmacological activity.

4. structural optimization Based on structure-activity relationship research, structural modification of GCA is carried out to enhance its activity, selectivity, and pharmacokinetic properties. Focus on the modification of the sugar moiety and the modification of the quinic acid backbone.

5. Formulation development Explore new drug delivery systems (such as nano formulations, phospholipid complexes, self microemulsifying drug delivery systems) to improve the bioavailability of GCA.

6. Preclinical evaluation Conduct systematic pharmacological and toxicological studies to validate the therapeutic efficacy and safety of GCA in various animal models, laying the foundation for clinical trials.

Conclusion

5-O - [4 '- O - (β - D-glucopyranosyl) caffeoyl] quinic acid, as a structurally unique glycosylated caffeoyl quinic acid, represents an interesting member of the chemical diversity of natural products. Its molecular structure combines three basic units: quinic acid, caffeic acid, and glucose, endowing the compound with rich chemical properties and diverse biological activities. Current research indicates that GCA has various pharmacological activities such as antioxidant, anti-inflammatory, antibacterial, and antiviral effects, and its mechanism of action involves multiple signaling pathways such as NF - κ B, MAPK, and Nrf2.

However, research on GCA is still in its infancy, and many key issues need to be addressed. The limited plant sources, low bioavailability, and unclear mechanism of action pose challenges to its further development and application. In the future, with the deepening of biotechnology, medicinal chemistry, and pharmacology research, GCA is expected to overcome existing shortcomings through structural optimization and formulation innovation, and develop into a candidate drug with clinical application value.

Natural products have always been an important source of drug discovery, and structurally novel natural products are valuable resources for the creation of new drugs. The research on GCA not only helps to reveal the biological functions of glycosylated polyphenolic compounds in nature, but also provides lead molecules for the development of new anti-inflammatory and antioxidant drugs. We look forward to the near future, with the continuous deepening of research, GCA can play its due value in human health maintenance and disease treatment.