Product name: 3,5-Dicaffeoylquinic acid
Synonym name: Isochlorogenic acid A
Catalogue No.: BP0056
Cas No.: 2450-53-5
Formula: C₂₅H₂₄O₁₂
Mol Weight: 516.455
Botanical Source: globe artichoke (Cynara scolymus), quince fruit (Cydonia oblonga), Caucasian whortleberry (Vaccinium arctostaphylos), Aster scaber and Ipomoea batatas (sweet potato) tubers
Physical Description: White powder
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, up to kilograms
Inquire for bulk scale.

Descriptions:
Isochlorogenic acid A possesses the potent anti-hepatitis B activity and anti-HBV activity, could be achieved by its antioxidative property and induction of HO-1.[1]
Metabolic processes of isochlorogenic acid A in rats conform to linear dynamics with fast metabolism and short half-life.[2]

References:
[1] Hao B J, Wu Y H, Wang J G, et al. J Ethnopharmacol, 2012, 144(1):190-4.
[2] Cheng X G, Wang S J, Zeng J, et al. Chinese Journal of Experimental Traditional Medical Formulae, 2015(16):79-82.
[3] Li Xiangyang, Tu Wanqian. Chinese medicine, 2014, 36 (02): 353-8.

HPLC of Isochlorogenic acid A

HNMR of Isochlorogenic acid A

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

Introduction/Overview

Natural products, as an important treasure trove for drug discovery and development, play an irreplaceable role in the long history of human fight against diseases. Among them, phenolic acid compounds have always been a hot topic in medicinal chemistry and pharmacology research due to their extensive and significant biological activities. Isochlorogenic acid A (3,5-Dicaffeoylquinic acid, 3,5-DCQA), as a member of the chlorogenic acid compound family, has attracted much attention in recent years due to its diverse pharmacological effects and potential therapeutic value. This compound was first isolated from Brazilian propolis and various medicinal plants (such as Suaeda salsa), and its unique chemical structure endows it with multiple biological activities such as antioxidant, anti-inflammatory, antiviral, anti-tumor, and hepatoprotective. With the development of modern molecular biology and network pharmacology, the study of the mechanism of action of isochlorogenic acid A has deepened from the traditional single target to the multi target and multi pathway synergistic mode. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, pharmacological evaluation, and clinical application prospects of isochlorogenic acid A, in order to provide comprehensive scientific references for the deep development and transformation of this natural product.

Chemical structure and physicochemical properties

The chemical name of isochlorogenic acid A is 3,5-dicaffeoylquinic acid, and its CAS number is 2450-53-5. Structurally, it is composed of a quinic acid (a cyclic polyol carboxylic acid) as the central skeleton, which is condensed with the carboxyl groups of two trans caffeic acids through ester bonds on its 3rd and 5th hydroxyl groups, respectively. Therefore, it belongs to the class of carboxylic acid esters and cyclic alcohol carboxylic acid compounds. Its molecular formula is C25H24O12 and its molecular weight is 516.4550.

The caffeoyl group in its structure is the key pharmacophore that endows it with biological activity. Caffeic acid itself has a phenolic hydroxyl structure and is a potent antioxidant group. The introduction of two caffeoyl groups results in the enrichment of phenolic hydroxyl groups in the molecule of isochlorogenic acid A, which determines its significant antioxidant and free radical scavenging abilities. From the analysis of physical and chemical properties, the calculated lipid water partition coefficient (LogP) is about 1.19, indicating that it has a certain degree of lipophilicity, but overall it still leans towards hydrophilicity. Its topological polar surface area (TPSA) is as high as 211.28 Å ², which is mainly attributed to the numerous hydrogen bond receptors (ester and hydroxyl groups) in the molecule. This characteristic also indicates its strong hydration ability and relatively poor cytoplasmic membrane permeability. The calculated data shows that its water solubility is about 0.72 mg/mL, which is slightly soluble. These physicochemical parameters collectively affect its pharmacokinetic behavior, for example, its higher TPSA and polarity result in a predicted "low" blood-brain barrier permeability, meaning it is less likely to enter the central nervous system. In addition, preliminary pharmacological risk assessment showed that the hERG channel inhibition risk was negative, and the Ames mutagenicity test predicted a value of 0.0, suggesting that it may have good cardiac safety and low genetic toxicity risk, laying a good safety foundation for its further development.

Plant sources and extraction methods

Isochlorogenic acid A is widely distributed in nature and mainly exists in various Asteraceae, Lonicera, and propolis plants. Among them, Brazilian propolis (especially green propolis) is one of its most famous sources and the main material for early research and isolation of this compound. In addition, traditional medicinal plants such as Suaeda salsa（Suaeda spp.）、 Honeysuckle (Lonicera japonica), chrysanthemum (Chrysanthemum morifolium), coffee beans, and many vegetables and fruits (such as thistle and potato peel) have been detected.

The extraction of isochlorogenic acid A from plant materials mainly depends on its polarity and solubility. The conventional extraction methods include:
1. Solvent extraction method The most commonly used method. Usually, medium polarity solvents such as methanol, ethanol, or acetone aqueous solutions (such as 70% -80% ethanol) are used for extraction, reflux, or ultrasound assisted extraction. This method has high efficiency and relatively low cost.
2. Hot water extraction method By utilizing its certain solubility in water, but the extraction rate is usually lower than that of organic solvent methods, and more impurities such as polysaccharides and proteins may be extracted.
3. Modern extraction techniques In order to improve extraction efficiency and selectivity, techniques such as microwave-assisted extraction (MAE), ultrasound assisted extraction (UAE), and supercritical fluid extraction (SFE, commonly using CO ₂ and adding entrainers such as ethanol) have been applied. These methods can shorten extraction time, reduce solvent consumption, and potentially obtain higher purity extracts.

The crude extract after extraction usually requires further separation and purification to obtain high-purity isochlorogenic acid A. Common purification techniques include:
* Macroporous adsorption resin chromatography By utilizing the adsorption characteristics of phenolic acid compounds by resins such as AB-8, D101, HP-20, gradient elution with water and different concentrations of ethanol can effectively enrich isochlorogenic acid A.
* Silica gel column chromatography Gradient elution using mixed solvent systems such as chloroform methanol and dichloromethane methanol is a commonly used separation method in laboratories.
* Preparation type high performance liquid chromatography (HPLC)This is the most effective method for obtaining high-purity monomeric compounds, typically using a reverse phase C18 chromatography column with methanol water or acetonitrile water (often containing small amounts of formic acid or acetic acid to adjust pH) as the mobile phase for separation.
* High Speed Counter Current Chromatography (HSCCC)A liquid-liquid distribution chromatography technique that does not require a solid phase carrier and is suitable for preparing quantitative separations. It has unique advantages in separating isomers of isochlorogenic acid.

Pharmacological activity research

A large number of pharmacological studies both in vitro and in vivo have shown that isochlorogenic acid A has broad and significant biological activities.

1. antioxidant activity This is one of its most fundamental and important activities. The multiple phenolic hydroxyl groups in its molecule can effectively scavenge DPPH radicals, ABTS ⁺ radicals, superoxide anions, and hydroxyl radicals, and have significant iron ion reduction ability. Its antioxidant efficacy is stronger than that of single caffeic acid or quinic acid, reflecting the synergistic effect of its structure.
2. anti-inflammatory activity In various inflammatory cell models (such as lipopolysaccharide induced RAW264.7 macrophages) and animal models (such as mouse ear swelling and colitis models), isochlorogenic acid A can significantly inhibit the production of pro-inflammatory mediators such as nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor - α (TNF - α), interleukin-6 (IL-6), and IL-1 β. Its anti-inflammatory effect is closely related to the inhibition of the activation of nuclear factor kappa B (NF - κ B) and mitogen activated protein kinases (MAPKs) signaling pathways.
3. Hepatoprotective activity Research has confirmed that isochlorogenic acid A has a clear protective effect on various chemical liver injuries, such as acetaminophen, carbon tetrachloride, and D-galactosamine induction. It can reduce the levels of transaminase (ALT/AST) in serum, alleviate pathological damage to liver tissue, and its mechanism involves antioxidant stress, inhibition of inflammatory response, and resistance to liver cell apoptosis.
4. Antiviral activity Isochlorogenic acid A exhibits broad-spectrum antiviral potential. It has been reported that it can inhibit the replication of hepatitis B virus (HBV) DNA and HIV integrase. In addition, it can also inhibit influenza virus and herpes virus. Its mechanism of action may include interfering with virus adsorption, entry, or replication processes.
5. Antitumor and Cytotoxicity: Isochlorogenic acid A shows selective cytotoxicity to a variety of human cancer cell lines (such as HepG2, breast cancer MCF-7, lung cancer A549, colon cancer HT-29, etc.), and can inhibit the proliferation, migration and invasion of tumor cells, and induce cell cycle arrest and apoptosis. It is worth noting that its toxicity to normal cells is relatively low, indicating a certain therapeutic window.
6. Other activities It also includes antibacterial properties (with certain inhibitory effects on Staphylococcus aureus, Escherichia coli, etc.), anti mutation properties, neuroprotection, and improvement of insulin resistance. Its potential role in the cardiovascular system, especially its correlation with heart failure, is becoming a new research focus.

Mechanism of action and molecular targets

The pharmacological effects of isochlorogenic acid A are not achieved through a single target, but exhibit a network regulatory feature of multi-target and multi pathway synergy, which is in line with the characteristics of natural product action. Based on its known activity, especially its association with diseases such as heart failure, its potential targets and pathways include:

1. AMPK signaling pathway (target: PRKAA1)AMP activated protein kinase is a core regulator of cellular energy metabolism. Activation of AMPK can promote fatty acid oxidation, glucose uptake, inhibit protein and lipid synthesis, and is crucial for maintaining energy metabolism homeostasis in myocardial cells. Isochlorogenic acid A may improve the energy depletion of myocardial cells in heart failure by activating AMPK, which may be one of the core mechanisms of its potential heart failure protective effect.
2. Epigenetic regulation (target: EHMT2/G9a)Histone methyltransferase EHMT2 (G9a) catalyzes the dimethylation of histone H3 lysine 9 (H3K9me2), which is typically associated with gene transcription inhibition. Inhibiting G9a can reactivate the expression of certain protective genes. G9a may be involved in the process of cardiac remodeling and fibrosis. It is worth exploring whether isochlorogenic acid A regulates myocardial gene expression by affecting G9a activity.
3. Inflammation and oxidative stress pathway As mentioned earlier, its strong antioxidant and anti-inflammatory effects are mainly achieved by regulating classic pathways such as NF - κ B, MAPK (p38, JNK, ERK), Nrf2/HO-1. Inhibition of ALOX15 (15 lipoxygenase) may reduce the production of pro-inflammatory and pro apoptotic leukotrienes, which is a supplement to its anti-inflammatory mechanism.
4. Neuroendocrine and Signal Transduction Targets related to the pathology of heart failure, such as APP(Starch precursor protein, whose metabolic abnormalities are related to myocardial amyloidosis and functional impairment)PTPN1(Protein tyrosine phosphatase 1B, negatively regulating insulin and leptin signaling, associated with metabolic cardiomyopathy)MAOA Monoamine oxidase A catalyzes the degradation of catecholamines, and its overactivation leads to oxidative stress and myocardial injury ESR2 Estrogen receptor beta, which has a protective effect on cardiovascular health, may become an indirect or direct node of action for isochlorogenic acid A.
5. Drug efflux pump (targets: ABCB1/P-gp, ABCG2/BCRP)Isochlorogenic acid A has been reported as a substrate or weak inhibitor of these efflux pumps. This mainly affects its own pharmacokinetics (such as oral bioavailability, blood-brain barrier penetration) and its interactions with other drugs transported through this pathway, rather than direct therapeutic targets.

In summary, isochlorogenic acid A may form a synergistic network by simultaneously acting on multiple targets such as AMPK (improving energy metabolism), inhibiting inflammatory oxidative pathways (reducing myocardial injury), regulating related enzymes and receptors (such as MAOA, ESR2), and jointly exerting potential therapeutic effects on complex diseases such as heart failure.

Evaluation of drug properties and pharmacokinetics

Although isochlorogenic acid A has a wide range of pharmacological activities, its medicinal properties still face some challenges, mainly due to its chemical structural characteristics.

• absorb As a polar molecule containing multiple phenolic hydroxyl groups and ester bonds, its oral bioavailability may be low. This is mainly limited by gastrointestinal stability (ester bonds may be hydrolyzed), poor intestinal permeability (high TPSA), and possible first pass effects (metabolized by the intestine and liver). Studies have shown that the absolute bioavailability of chlorogenic acid compounds in rats is less than 5%.
• distribution Its predicted blood-brain barrier permeability is low, which limits its direct application in central nervous system diseases. But in peripheral tissues such as the liver, heart, etc., a certain distribution can still be achieved.
• Metabolism Isochlorogenic acid A undergoes hydrolysis metabolism in the body, where ester bonds are hydrolyzed by carboxylesterases and other enzymes to produce caffeic acid and quinic acid or their monoester derivatives. These metabolites themselves also have biological activity and may collectively contribute to the overall efficacy of the drug. Secondly, phenolic hydroxyl groups may undergo glucuronidation and sulfation reactions, generating more water-soluble complexes that are easier to excrete.
• excretion The prototype drug and its metabolites are mainly excreted through the kidneys and urine.
• Optimization strategy for drug properties In order to enhance its medicinal properties, researchers are exploring various strategies:
  • Structural modification By preparing prodrugs (such as esterified phenolic hydroxyl groups to improve lipid solubility and membrane permeability), and preparing phospholipid complexes or metal complexes, their solubility and stability can be improved.
  • New drug delivery system The use of nanotechnology, such as liposomes, nanoparticles, micelles, solid dispersions, etc., to encapsulate isochlorogenic acid A can significantly improve its solubility, protect it from premature degradation, enhance targeting, and potentially improve its oral absorption and bioavailability.
  • combination therapy When used in combination with other drugs that have synergistic effects, reducing the required dosage for each may bypass the limitation of low bioavailability as a single drug.

Clinical application prospects and prospects

The diverse pharmacological activities of isochlorogenic acid A provide broad prospects for its application in multiple therapeutic fields.

1. Adjuvant therapy for cardiovascular diseases, especially heart failure Developing plant-based drugs or dietary supplements for the treatment of chronic heart failure (especially ejection fraction preserved heart failure) based on their potential multi-target effects such as AMPK activation, anti-inflammatory and antioxidant effects, and regulation of neuroendocrine functions is a highly attractive direction. Consider combining with existing standard treatment drugs to achieve synergistic effects and reduce side effects.
2. liver disease Its clear hepatoprotective effect makes it valuable for development in the prevention and treatment of drug-induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis (NASH), and can be used as a hepatoprotective preparation.
3. Antitumor adjuvant therapy As a naturally derived cytotoxic ingredient, it can be explored to be used in combination with chemotherapy drugs to enhance efficacy, reduce chemotherapy drug dosage and toxic side effects. Its antioxidant properties may also be used to alleviate oxidative damage to normal tissues caused by radiotherapy or chemotherapy.
4. Antiviral applications Although its activity intensity may not be as strong as synthetic drugs, its multi-target and low resistance potential make it promising for the development of broad-spectrum antiviral (such as anti influenza, anti herpes) natural drugs or functional foods.
5. Functional foods and cosmetics With excellent antioxidant and anti-inflammatory properties, isochlorogenic acid A can be used as a high-end functional food additive (for delaying aging, enhancing immunity) or cosmetic ingredient (for anti skin photoaging, soothing inflammation).

However, in order to achieve its true clinical translation, future research still needs to make breakthroughs in the following areas:
* In depth study on the mechanism of action Using techniques such as gene knockout/knock in, proteomics, metabolomics, etc., to accurately validate the multi-target network pharmacological mechanism in more complex disease animal models (such as pressure overload heart failure models).
* Preclinical and clinical research of the system Complete pharmacokinetic and toxicological (long-term toxicity, reproductive toxicity, etc.) evaluations that comply with international standards, and conduct rigorous randomized controlled clinical trials to confirm their effectiveness and safety in humans.
* Innovation in formulation technology Continuously developing efficient, stable, and targeted new delivery systems to solve the bottleneck problem of low bioavailability.
* Synthetic Biology Production Given the limited extraction content from plants and the influence of seasonal regions, exploring the use of microbial cell factories (such as yeast and Escherichia coli) for heterologous synthesis of isochlorogenic acid A is an important way to achieve its large-scale and sustainable supply.

Conclusion

As a naturally occurring polyphenolic acid compound, isochlorogenic acid A has shown great potential for transformation from traditional medicinal resources to modern therapeutic drugs due to its extensive pharmacological activity and multi-target mechanism of action. From chemical structure to plant origin, from basic antioxidant and anti-inflammatory properties to exploring the deep mechanisms of complex diseases such as heart failure, research continuously reveals its value as a "versatile" molecule. Despite facing challenges such as bioavailability in drug development, these obstacles are gradually being overcome through the cross fusion of modern medicinal chemistry, pharmacy, and synthetic biology. In the future, with deeper basic research and rigorous clinical verification, isochlorogenic acid A is expected to realize its application value in cardiovascular protection, liver disease prevention and treatment, tumor adjuvant therapy, and major health products, contributing a gift from nature to human health.