Introduction/Overview
Natural products have always been an important treasure trove for innovative drug discovery, among which flavonoids have attracted much attention due to their broad biological activity and low toxicity. Quercetin Dihydrate (CAS number: 6151-25-3), as a common hydrated form of quercetin, is one of the most abundant flavonols in the diet, widely present in fruits, vegetables, tea, and various medicinal plants. The parent structure of quercetin (3,3 ', 4', 5,7-pentahydroxyflavone) is one of the most extensively studied flavonoids. Modern pharmacological research has shown that quercetin dihydrate not only has strong antioxidant capacity, but also exhibits unique pharmacological properties of multi-target and multi pathway regulation. It can play a core regulatory role in physiological and pathological processes such as cell metabolism, inflammatory response, cell proliferation, and apoptosis by activating various key signaling proteins such as SIRT1 and inhibiting PI3K. This article aims to systematically review the chemical properties, plant sources, pharmacological activities, molecular mechanisms of action, pharmacological evaluation, and clinical application potential of quercetin dihydrate, in order to provide comprehensive scientific references for the deep development and transformation research of this natural product.
Chemical structure and physicochemical properties
The chemical name of dihydrate quercetin is 3,3 ', 4', 5,7-pentahydroxyflavone dihydrate, with a molecular formula of C ₁₅ H ₁₀ O ₇· 2H ₂ O and a molecular weight of 302.2380 (calculated as anhydrous quercetin, the actual molecular weight is higher after adding crystalline water). Its basic skeleton is the classic flavonoid nucleus, which is composed of two benzene rings (A ring and B ring) connected by an oxygen-containing heterocyclic ring (C ring). Its structural feature is that the 5,7 positions of the A ring and the 3 ', 4' positions of the B ring are both replaced by hydroxyl groups, and there is also a hydroxyl group at the 3 position of the C ring. This catechol structure and multiple phenolic hydroxyl groups are the chemical basis for its strong antioxidant activity.
In terms of physical and chemical properties, quercetin dihydrate is a yellow crystalline powder. Its lipid water partition coefficient (LogP) is about 1.94, indicating that it has a certain lipophilicity, but not highly lipophilic. The topologically polar surface area (TPSA) is as high as 131.36 Å ², which is mainly attributed to the numerous hydroxyl and carbonyl groups in its molecules. These polar groups also result in poor water solubility, about 0.0767 mg/mL, which to some extent limits its bioavailability. The compound showed a result of 0.6 in the Ames test, indicating a low risk of mutagenicity. In addition, it has no significant inhibitory effect on hERG potassium channels, indicating a lower potential risk of arrhythmia. However, its blood-brain barrier permeability was evaluated as' low ', suggesting that its direct therapeutic effect on central nervous system diseases may be limited and needs to be improved through dosage form modifications or structural modifications.
Plant sources and extraction methods
Quercetin dihydrate is widely distributed in nature, mainly in the form of glycosides (such as rutin, isoquercitrin, etc.) in various plants, with relatively less free quercetin and its hydrates. Plant sources rich in quercetin glycosides include onions (especially red skinned onions), apples, berries (such as cranberries and blueberries), broccoli, tea (especially green tea), ginkgo leaves, forsythia suspensa (St. John's wort), and various traditional Chinese medicines such as locust flowers and mulberry leaves. The quercetin glycosides in these plants can be hydrolyzed by human gut microbiota or plant enzymes to produce bioactive quercetin.
The solvent extraction method is commonly used to extract quercetin dihydrate or its glycosides from plant materials. Ethanol water system is the most commonly used solvent due to its good selectivity towards flavonoids, low toxicity, and moderate cost. The specific process usually includes: heating and refluxing the dried and crushed plant materials with a certain concentration of ethanol (such as 60% -80%) or ultrasound assisted extraction. After filtration and concentration, the extract can be enriched and purified using macroporous adsorption resins (such as AB-8 and D101). By utilizing the adsorption desorption characteristics of quercetin compounds and resins, and using water and different concentrations of ethanol gradient elution, high-purity quercetin glycoside components can be obtained. To obtain free crystals of quercetin dihydrate, the glycoside extract needs to be subjected to acid hydrolysis or enzymatic hydrolysis to break the glycosidic bond and release quercetin aglycones. Then, steps such as recrystallization can be performed to obtain pure quercetin dihydrate. Modern extraction techniques such as supercritical CO ₂ extraction, microwave-assisted extraction, and high-voltage pulsed electric field extraction are also constantly being explored to improve extraction efficiency and protect active ingredients.
Pharmacological activity research
The pharmacological activity research of quercetin dihydrate has accumulated decades of evidence, and its effects are extensive and complex. The core activities can be summarized as follows:
-
Excellent antioxidant and anti-inflammatory activity This is the most fundamental and important activity of quercetin dihydrate. It can directly eliminate various reactive oxygen/nitrogen species such as superoxide anions, hydroxyl radicals, and peroxynitrite. Its mechanism of action includes providing hydrogen atoms or electrons to neutralize free radicals, as well as chelating transition metal ions (such as Fe ² ⁺, Cu ² ⁺) to prevent Fenton reaction. More importantly, it can indirectly resist oxidation by activating the cell's own antioxidant defense system. Its strong antioxidant capacity is the cornerstone of its anti-inflammatory, anti atherosclerosis, neuroprotective and other downstream effects.
-
Antitumor activity A large number of in vitro and animal model studies have shown that quercetin dihydrate can inhibit the growth and promote apoptosis of many cancer cell lines (such as breast cancer, lung cancer, prostate cancer, colon cancer, etc.). Its anti-tumor mechanism is multifaceted, including inducing cell cycle arrest (often in G1 or G2/M phase), mitochondrial mediated apoptosis, inhibiting tumor cell invasion and metastasis, suppressing tumor angiogenesis, and acting as a chemical sensitizer to enhance the efficacy of traditional chemotherapy drugs.
-
Cardiovascular protective effect Quercetin dihydrate plays an anti atherosclerotic role by improving endothelial function, inhibiting low-density lipoprotein oxidation, reducing vascular inflammation, anti platelet aggregation, and regulating blood pressure (such as inhibiting the activity of angiotensin converting enzyme). Epidemiological studies suggest that a diet rich in quercetin is associated with a reduced risk of coronary heart disease.
-
Metabolic regulation effect Research shows that quercetin dihydrate can improve insulin resistance, reduce blood sugar level, and has potential preventive and therapeutic effects on diabetes and its complications. It can also regulate lipid metabolism, reduce serum total cholesterol and triglycerides.
-
Neuroprotective effect Despite its limited blood-brain barrier permeability, studies have shown that quercetin dihydrate can alleviate beta amyloid induced neurotoxicity and inhibit excessive activation of microglia through its antioxidant and anti-inflammatory properties, demonstrating protective effects in animal models of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease.
Mechanism of action and molecular targets
The multiple pharmacological activities of quercetin dihydrate stem from its precise regulation of multiple key signaling molecules and pathways within cells, and its mechanism of action is complex and orderly.
-
Activate SIRT1 pathway SIRT1 is a NAD ⁺ - dependent class III histone deacetylase that plays a central role in energy metabolism, stress resistance, aging, and inflammation. Quercetin dihydrate has been confirmed to be an activator of SIRT1. The activation of SIRT1 can lead to the deacetylation and activation of downstream targets such as PGC-1 α and FOXO transcription factors, thereby upregulating mitochondrial biosynthesis, enhancing antioxidant defense (such as inducing SOD2 expression), promoting autophagy, and inhibiting NF - κ B-mediated inflammatory responses. This is one of the core mechanisms by which it exerts anti-aging, metabolic regulation, and cell protection effects.
-
Inhibition of PI3K/Akt/mTOR pathway Quercetin dihydrate is a natural inhibitor of PI3K, and its inhibitory activity against different subtypes of PI3K (γ, δ, β) (IC50 values at the micromolar level) has been quantified. The PI3K/Akt/mTOR pathway is a core signaling axis that regulates cell growth, proliferation, metabolism, and survival, and is often overactivated in cancer and metabolic diseases. By inhibiting PI3K, quercetin dihydrate can block the phosphorylation activation of Akt, thereby inhibiting downstream targets such as mTOR, ultimately leading to cell cycle arrest, induction of apoptosis, and autophagy. This is an important molecular basis for its anti-tumor and metabolic regulation.
-
Regulating Nrf2/ARE antioxidant defense system Facing oxidative stress, quercetin dihydrate can stabilize nuclear factor E2 related factor 2 (Nrf2) and promote its translocation from the cytoplasm to the nucleus. In the nucleus, Nrf2 binds to antioxidant response elements (ARE) and initiates the transcription of a series of phase II detoxifying enzymes and antioxidant proteins, including heme oxygenase-1 (HMOX1), superoxide dismutase (SOD1, SOD2), catalase (CAT), glutathione peroxidase (GPX1), etc. This systematic defense network enhancement is the key to achieving indirect and long-lasting antioxidant effects of quercetin dihydrate.
-
Regulating the inflammatory signaling pathway In addition to indirectly inhibiting NF - κ B by activating SIRT1, quercetin dihydrate can also directly interfere with the activation process of NF - κ B, inhibit the activity of I κ B kinase (IKK), prevent the degradation of I κ B and nuclear translocation of NF - κ B p65 subunit, thereby downregulating the expression of pro-inflammatory cytokines such as TNF - α, IL-1 β, IL-6, etc. Meanwhile, it can also inhibit the production of inflammatory mediators such as COX-2 and iNOS.
-
Other targets Quercetin dihydrate can also affect the MAPK pathway, Wnt/β - catenin pathway, epigenetic modifying enzymes (such as histone acetyltransferase/deacetylase, DNA methyltransferase), etc., forming a highly interconnected regulatory network.
Evaluation of drug properties and pharmacokinetics
Despite the excellent pharmacological activity of quercetin dihydrate, its drug likeness faces challenges, mainly reflected in its pharmacokinetic properties.
absorb After oral administration, quercetin glycosides (such as rutin) have limited absorption in the upper small intestine and are mainly absorbed in the large intestine after hydrolysis by gut microbiota into aglycones. The oral bioavailability of free quercetin dihydrate itself is relatively low (usually reported to be<2%), due to poor water solubility, instability in the gastrointestinal tract, significant first pass metabolic effects, and possible interactions with intestinal contents or gut microbiota.
distribution After absorption, quercetin rapidly binds to albumin in plasma and is widely distributed in various tissues throughout the body, but the concentration varies greatly in different tissues. Its low blood-brain barrier permeability limits its direct action in the central nervous system.
Metabolism Quercetin undergoes extensive metabolic transformation in the body. The main metabolic sites are in the liver and intestines, and metabolic reactions include glucuronidation, sulfation, and methylation, producing various metabolites (such as quercetin-3-O-glucuronic acid glycoside, quercetin-3 '- sulfate, etc.). These metabolites are usually less active than the prototype drug, but some still retain some biological activity.
excretion Quercetin and its metabolites are mainly excreted through urine and bile, with a relatively short half-life (about 3-4 hours).
Optimization strategy for drug properties To improve its bioavailability and efficacy, researchers have developed various strategies: ① Formulation improvement For example, preparing nanocrystals, liposomes, solid dispersions, phospholipid complexes, cyclodextrin inclusion complexes, etc., to increase solubility and stability and promote absorption. ② Structural modification Synthesize prodrugs or derivatives of quercetin to improve its physicochemical properties and metabolic stability. ③ combination therapy Combined with substances such as vitamin C and piperine, the latter can inhibit the metabolic enzymes of quercetin or increase its absorption.
Clinical application prospects and prospects
The potential of quercetin dihydrate from laboratory research to clinical application is enormous, but its transformation pathway requires scientific planning and rigorous validation.
Current applications and clinical trials At present, quercetin dihydrate/quercetin is mainly circulated in the market as a dietary supplement and functional food ingredient, claiming to have antioxidant, anti-inflammatory, and immune enhancing effects. At the clinical research level, hundreds of clinical trials have been registered to explore their applications in the following fields: ① Metabolic syndrome and cardiovascular disease As an auxiliary measure, improve blood pressure, blood lipids, and endothelial function. ② Cancer adjuvant therapy Combined with chemotherapy/radiotherapy, aimed at reducing side effects and increasing sensitivity to therapeutic effects. ③ Inflammatory diseases Take advantage of its anti-inflammatory properties, such as osteoarthritis and chronic prostatitis. ④ Sports Medicine Used to alleviate oxidative damage and muscle fatigue after exercise. However, most clinical trials are small in scale, with inconsistent results, and there is still a lack of large-scale, multi center, long-term follow-up confirmatory studies.
Future development direction：
1. Precision Targeted Delivery System: Develop a targeted delivery system based on nanotechnology, specifically deliver quercetin dihydrate to tumor tissue, inflammatory site or atherosclerotic plaque, increase local concentration and reduce systemic side effects.
2. Mechanism based combination therapy: Deeply study the synergistic mechanism between the drug and existing drugs (such as chemotherapy drugs, immunocheckpoint inhibitors, SGLT2 inhibitors, etc.), and design a reasonable combination drug scheme for complex diseases such as cancer, diabetes complications, etc.
3. Structural optimization and new drug development Using it as a lead compound, conduct systematic structural modification and structure-activity relationship research, develop synthetic derivatives with higher activity, better selectivity, and better pharmacokinetic properties, and create new chemical solid drugs.
4. In depth mechanism and biomarker research Using systems biology and computational biology methods, comprehensively analyze its multi-target action network, and search for biomarkers that can predict its efficacy and toxicity, achieving personalized medication.
5. Expand the exploration of indications Given its ability to activate SIRT1 and inhibit PI3K, it has broad exploration potential in fields such as aging related diseases, neurodegenerative diseases, and fibrotic diseases.
Conclusion
As a classic natural flavonoid compound, the research process of quercetin dihydrate can be regarded as a microcosm of natural product pharmacology. From its initial antioxidant properties to now being revealed as a multi-target regulator capable of simultaneously regulating multiple key signaling nodes such as SIRT1, PI3K, Nrf2, its scientific connotation continues to enrich. The "one stone, many birds" biological effects it exhibits provide highly attractive intervention strategies for dealing with complex multifactorial diseases such as cancer, metabolic diseases, and chronic inflammation. Although its inherent pharmaceutical defects, such as low solubility and low bioavailability, are the main bottlenecks facing clinical translation, the rapid development of modern pharmacy, medicinal chemistry, and nanotechnology is providing powerful tools to overcome these obstacles. In the future, through deep interdisciplinary integration and innovation, quercetin dihydrate is expected to transform from a well-known dietary ingredient into a modern drug based on clear molecular mechanisms, or at least become an important component of optimized treatment plans, playing a more substantial role in human health maintenance and disease prevention and control. The continuous and in-depth research on it not only has important scientific value, but also contains enormous social and economic potential.
