Introduction/Overview
Natural products, as an important treasure trove for drug discovery, play an irreplaceable role in the history of human disease prevention and treatment. Among them, active ingredients derived from traditional medicinal plants have become a key source of lead compounds for modern innovative drug development due to their structural diversity and rich biological activity. Rutaevin (CAS number: 33237-37-5) is a highly regarded natural molecule. It is mainly derived from the traditional Chinese medicine Rutaceae plant Evodia rutaecarpa（Euodia rutaecarpa）It was isolated and early studies revealed that it has significant anti-inflammatory activity, which can inhibit the excessive production of nitric oxide (NO) in macrophages induced by lipopolysaccharide (LPS). In recent years, with the deepening of research, the pharmacological spectrum of Evodia rutaecarpa extract has been continuously expanded, especially in the field of anti-tumor, showing great potential. Its inhibitory effect and related molecular mechanisms in various malignant tumors such as gastric cancer have been gradually revealed. This article aims to systematically review the chemical structure, plant origin, pharmacological activity, mechanism of action, pharmacological characteristics, and clinical application prospects of Wu Zhu Ku Su, in order to provide comprehensive scientific references for the in-depth research and development of this compound.
Chemical structure and physicochemical properties
Wu Zhu Ku Su is a tetracyclic triterpenoid compound with a molecular formula of C27H34O9 and a molecular weight of 486.5170. Its core structure belongs to limonoid analogues, with a highly oxidized four ring skeleton and multiple oxygen-containing functional groups connected, such as hydroxyl, carbonyl, and lactone rings. These structural features are important material foundations for its biological activity.
From the analysis of physical and chemical properties, the lipid water partition coefficient (LogP) of Wu Zhu Ku Su is 1.6756, indicating that it has a certain lipophilicity, but not extreme hydrophobicity, which is conducive to its penetration of cell membranes. Its topological polar surface area (TPSA) is 124.8000 Å ², reflecting the larger area occupied by polar atoms in the molecule, which is consistent with the presence of multiple hydroxyl and carbonyl oxygen atoms in the structure. The water solubility parameter is 0.0273, indicating that it has low solubility in water and belongs to insoluble compounds, which may pose challenges in formulation development. It is worth noting that its blood-brain barrier permeability is predicted to be "high", suggesting that the compound may have the potential to act on the central nervous system. In the early safety screening, the hERG inhibition experiment resulted in negative results, reducing the possibility of inducing QT interval prolongation in the heart; The Ames test result is 0.9, indicating a low risk of mutagenicity and providing preliminary safety evidence for its further development.
Plant sources and extraction methods
The bitter extract from Wu Zhu Yu mainly comes from the traditional Chinese medicine Wu Zhu Yu, which belongs to the Rutaceae plant Wu Zhu Yu（Euodia rutaecarpa (Juss.) Benth.）、 Shihu（E. rutaecarpa var. officinalis）Or sparse haired Wu Zhuyu（E. rutaecarpa var. bodinieri）Dry and nearly ripe fruits. Wu Zhu Zhu has a long history of medicinal use in China, often used to treat symptoms such as headache, abdominal pain, vomiting, and hypertension.
The extraction and separation of bitter extract from Fructus Evodiae usually follow the conventional process of natural product chemistry. Firstly, the dried Fructus Evodiae fruit is crushed and subjected to reflux extraction or ultrasound assisted extraction using polar solvents such as methanol, ethanol, or aqueous ethanol to obtain the crude extract. Subsequently, using the system solvent extraction method (such as sequentially extracting with petroleum ether, ethyl acetate, and n-butanol), rutin is often enriched in the ethyl acetate extraction site due to its equipolarity. Further purification depends on a variety of chromatographic techniques, including silica gel column chromatography, reverse phase silica gel column chromatography (such as ODS), dextran gel column chromatography (such as Sephadex LH-20), and high performance liquid chromatography (HPLC). Through nuclear magnetic resonance (NMR), mass spectrometry (MS), and comparison with literature data, its chemical structure can be ultimately identified. Optimizing the extraction process (such as solvent ratio, temperature, time) and adopting modern technologies such as high-speed counter current chromatography (HSCCC) can help improve the yield and purity of rutin.
Pharmacological activity research
Wu Zhu Ku Su exhibits various pharmacological activities, and its research has expanded from its initial anti-inflammatory effects to multiple fields such as anti-tumor and antibacterial effects.
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anti-inflammatory activity This is one of the earliest reported activities of Wu Zhu Ku Su. Research has shown that it can significantly inhibit the expression of inducible nitric oxide synthase (iNOS) and NO production in LPS stimulated mouse Raw 264.7 macrophages. NO is a key mediator in the inflammatory response, and its excessive production is associated with various chronic inflammatory diseases. This activity suggests that Wu Zhu Ku Su has potential value in the treatment of inflammatory diseases.
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Antitumor activity This is currently the focus of research on the bitter extract from Fructus Evodiae, especially in the field of gastric cancer. In vitro and in vivo experiments have confirmed that Wu Zhu Ku Su can effectively inhibit the proliferation, migration, and invasion of various gastric cancer cell lines (such as SGC-7901, MKN-45), and induce cell apoptosis and cycle arrest. In addition, research suggests that it may also have inhibitory effects on other types of cancer, such as liver cancer and breast cancer, showing a broad spectrum anti-tumor potential.
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Other activities Preliminary studies have also found that Wu Zhu Ku Su has certain antibacterial and antioxidant activities, but its specific strength and mechanism of action still need to be further explored.
Mechanism of action and molecular targets
The anti-tumor effect of Wu Zhu Ku Su involves a complex regulatory network of multiple targets and pathways, especially in gastric cancer, and significant progress has been made in the study of its mechanism of action. According to the provided target information, its mechanism of action can be summarized as follows:
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Inducing apoptosis and regulating apoptosis related proteins Wu Zhu Ku Su can upregulate pro apoptotic proteins, while downregulating anti apoptotic proteins B cell lymphoma 2 (BCL2) and BCL2 like protein 1 (BCL2L1), thereby disrupting mitochondrial membrane potential, activating Caspase cascade reaction, and ultimately triggering tumor cell apoptosis.
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Inhibition of STAT3 signaling pathway Signal transduction and transcription activator 3 (STAT3) is an important oncogenic transcription factor. Wu Zhu Ku Su can inhibit the phosphorylation activation of STAT3, thereby downregulating the expression of downstream target genes such as BCL2 and MMP9, and inhibiting cell proliferation, survival, and metastasis.
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Affects MAPK and PI3K/AKT pathways Mitogen activated protein kinase 1 (MAPK1, also known as ERK2) and phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) are core signaling molecules that regulate cell growth, survival, and metabolism. Wu Zhu Ku Su may exert its growth inhibitory and pro apoptotic effects by intervening in these pathways.
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Inhibit tumor invasion and metastasis Matrix metalloproteinase 9 (MMP9) is a key enzyme that degrades extracellular matrix and promotes tumor invasion and metastasis. Wu Zhu Ku Su can downregulate the expression of MMP9, thereby inhibiting the migration and invasion ability of gastric cancer cells.
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Reverse multidrug resistance Overexpression of multidrug resistance protein 1 (ABCB1/P-gp) is an important cause of chemotherapy failure. Research has shown that quercetin from Fructus Evodiae may reverse drug resistance by inhibiting the function or expression of ABCB1, increasing the accumulation of chemotherapy drugs in tumor cells.
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Regulating oxidative stress and DNA damage Wu Zhu Ku Su may regulate cellular oxidative stress response by affecting the nuclear factor E2 related factor 2 (NFE2L2/Nrf2) pathway. Meanwhile, it may interfere with DNA replication and repair by acting on topoisomerase I (TOP1), leading to DNA damage and inhibiting tumor cell growth.
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Anti inflammatory and tumor microenvironment regulation Its ability to inhibit NO production is not only directly associated with anti-inflammatory effects, but may also indirectly exert anti-tumor effects by regulating immune cell functions such as tumor associated macrophages, affecting the tumor microenvironment.
These targets and pathways do not exist in isolation, but form an interconnected network. Wu Zhu Ku Su works synergistically on this network to achieve multidimensional strikes on gastric cancer cells.
Evaluation of drug properties and pharmacokinetics
Based on the provided pharmacological parameters and existing research, a preliminary evaluation of the pharmacological properties of Wu Zhu Ku Su is conducted
Advantage：
1. Clear activity and multi-target effects It has precise in vitro and in vivo anti-tumor activity, and its mechanism of action involves multiple key targets, which may help overcome the resistance problem of single target drugs.
2. Preliminary safety is good The negative results of hERG inhibition and Ames test are important positive signals for its early development.
3. Potential brain distribution Prediction of high blood-brain barrier permeability provides the possibility for its treatment of brain tumors or central nervous system related diseases.
challenge：
1. Poor water solubility The extremely low water solubility (0.0273) is the main obstacle facing its oral administration and formulation development. It may be necessary to improve its solubility and bioavailability through strategies such as salt formation, formation of inclusion complexes, nanocrystals, liposomes, or prodrug modification.
2. Lack of pharmacokinetic data At present, there are few reports on the systematic pharmacokinetic studies (such as absorption, distribution, metabolism, and excretion) of rutin in Fructus Evodiae. Key information such as metabolic stability, major metabolites, half-life, and tissue distribution characteristics in its body urgently need to be clarified. Its LogP value suggests that it may be widely metabolized by the cytochrome P450 enzyme system.
3. The selectivity needs further verification Although it has an inhibitory effect on cancer cells, its toxicity to normal cells (therapeutic window) needs to be thoroughly evaluated to ensure its safety.
Clinical application prospects and prospects
As a natural compound with multi-target anti-tumor activity, the clinical application prospects of Wu Zhu Ku Su are mainly reflected in the following aspects:
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Candidate drugs for anti gastric cancer Given its significant efficacy in gastric cancer models and its regulatory effects on key gastric cancer related targets such as STAT3, BCL2, ABCB1, etc., Wu Zhu Ku Su is most promising for development as a novel anti gastric cancer drug, especially for adjuvant chemotherapy or treatment of drug-resistant gastric cancer.
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Chemosensitizer Its potential reversal of ABCB1 mediated multidrug resistance makes it promising to be used in combination with conventional chemotherapy drugs such as paclitaxel and doxorubicin to improve chemotherapy efficacy and overcome clinical resistance challenges.
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Combination therapy strategy Based on its multi pathway regulatory characteristics, the combination of drugs targeting PI3K/AKT, MAPK and other pathways may produce synergistic effects and delay the emergence of drug resistance.
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Treatment of inflammation related diseases Its anti-inflammatory activity also provides exploration direction for its application in chronic inflammatory diseases such as colitis and arthritis.
However, pushing it from a lead compound to clinical practice still faces a series of challenges and future research directions:
* In depth mechanism research It is necessary to use techniques such as gene knockout/knockdown, chromatin immunoprecipitation, proteomics, etc. to more accurately elucidate its direct targets and upstream and downstream signaling networks.
* Optimization of drug properties in the system Comprehensive preclinical pharmacokinetic and toxicological studies must be conducted. It is crucial to conduct systematic pharmaceutical research to address its poor water solubility.
* Structural modification and development of analogues Using it as the parent nucleus for structural modification, with the aim of enhancing activity, improving solubility, and reducing potential toxicity, is an important direction in pharmaceutical chemistry research.
* Conduct standardized preclinical and clinical research After completing sufficient pharmacological, pharmacokinetic, and toxicological evaluations, it is necessary to gradually promote standardized clinical trials to verify its safety and efficacy in humans.
Conclusion
Wu Zhuyu Ku Su is a type of limonoid compound with important biological activity isolated from traditional Chinese medicine Wu Zhuyu. From the initial discovery of anti-inflammatory effects to the multi-target and multi pathway inhibition mechanisms demonstrated in the field of anti-tumor research, especially in the study of gastric cancer, its research value is increasingly prominent. It can not only regulate key signaling pathways such as BCL2, STAT3, MAPK, PI3K, induce tumor cell apoptosis, inhibit proliferation and metastasis, but also possibly reverse multidrug resistance, with broad development prospects. Despite facing challenges such as poor water solubility and lack of systematic pharmacokinetic data in drug development, these obstacles are expected to be overcome through the intervention of modern medicinal chemistry, pharmacology, and pharmacology methods. In the future, in-depth exploration of the mechanism, optimization of drug properties, and clinical translation research around Wu Zhu Ku Su will provide a new natural source candidate drug or treatment strategy for the treatment of malignant tumors such as gastric cancer, demonstrating the enormous potential of exploring modern therapeutic drugs from the treasure trove of traditional medicine.
