Introduction/Overview
As a highly malignant digestive system tumor, pancreatic cancer is famous for its insidious onset, rapid progress and poor prognosis. The five-year survival rate is less than 10% for a long time, and it is known as the "king of cancer". Although considerable progress has been made in surgical techniques, chemotherapy schemes (such as FOLFIRINOX, gemcitabine combined with albumin binding paclitaxel) and targeted treatment (such as PARP inhibitor for BRCA mutation) in recent years, the inherent resistance of pancreatic cancer to existing treatment methods and the biological characteristics of high invasion and metastasis make the clinical efficacy still far from reaching expectations. Therefore, finding new lead compounds with novel structure and unique mechanism of action from nature and developing new therapeutic drugs for pancreatic cancer is one of the frontier hotspots of current pharmaceutical chemistry and pharmacology research.
Natural products, especially alkaloids derived from medicinal plants, have always been an important source of anti-tumor drug discovery. Chelerythrine, as a classic benzophenanthrene alkaloid, is widely present in poppy plants and has been proven to have broad-spectrum anti-tumor activity. However, its significant toxic side effects and poor selectivity limit its clinical translation. In order to improve its pharmacological properties, researchers have synthesized a series of derivatives of quercetin through structural modification. Among them, 6- (5,6-dihydrochelerythrinyl) diamine (Bis [6- (5,6-dihydrochelerythrinyl)] amine, hereinafter referred to as "diamine derivative"), as a novel dimeric alkaloid derivative, exhibits unique chemical structure and potential biological activity.
This compound (CAS number: 165393-48-6) is composed of two 5,6-dihydroquercetin units connected by an amino bridge. This dimerization strategy aims to enhance the binding affinity with biological targets and may alter its pharmacokinetic characteristics. Preliminary computer simulation and in vitro experiments suggest that this compound may play an anti pancreatic cancer role through a multi-target regulatory network. Its potential targets include BCL2, which regulates apoptosis, TLR4, the transcription activator STAT3, the multidrug resistance protein ABCB1, egg white kinase C α (PRKCA), matrix metalloproteinase MMP2, the oxidative stress regulator NFE2L2, the ion channel TRPV1, topoisomerase TOP1, and the hypoxia inducible factor HIF1A. This multi target mode of action is expected to overcome the common single target drug resistance problem in the treatment of pancreatic cancer.
This article will systematically review 6- (5,6-dihydrocheleryl) diamine from the aspects of chemical structure, physical and chemical properties, plant sources and extraction methods, pharmacological activity, mechanism of action, pharmaceutical evaluation and clinical application prospects, aiming to provide a new perspective and theoretical basis for the research and development of natural drugs in the field of pancreatic cancer treatment.
Chemical structure and physicochemical properties
The chemical structure of 6- (5,6-dihydroquercetin) diamine has distinct characteristics. The parent nucleus of this compound is derived from Bai Qu Cai Hong alkaloid, which belongs to the benzophenanthrene alkaloid class. The core skeleton is a four ring system composed of a benzene ring and a phenanthrene ring fused together. In Bai Que Cai Hong alkaline, there is a double bond between the C5 and C6 positions of the phenanthrene ring, while in this derivative, the C5 and C6 positions are reduced to single bonds, forming 5,6-dihydroBai Que Cai Hong alkaline units. Two such units are connected to the C6 position through a bridged amino group (- NH -), forming a unique symmetrical dimer structure. This dimerization design is a common optimization strategy in natural product chemistry, aimed at increasing molecular volume and structural rigidity to enhance binding specificity and affinity with target proteins.
From the perspective of physical and chemical properties, the molecular formula of this compound is C42H41N3O8, with a molecular weight of 711.7710 Da, belonging to a medium to large molecule. Its lipid water partition coefficient (LogP) is 6.4815, indicating that the compound has extremely high lipid solubility and tends to be distributed in a lipid environment. This characteristic may be advantageous for it to penetrate the cell membrane and exert pharmacological effects inside the cell, but it may also lead to poor water solubility. Its topological polar surface area (TPSA) is 92.35 Å ², which is within the acceptable range for oral medication (usually<140 Å ²), indicating a certain potential for oral absorption, but a high LogP value may offset some of the advantages. The water solubility data is 0.0000, indicating that the compound is almost insoluble in water, which poses a serious challenge for its formulation development and may require the use of solubilization techniques such as liposomes, nanoparticles, cyclodextrin inclusion complexes, or prodrug design.
It is worth noting that the blood-brain barrier (BBB) penetration of this compound is predicted to be "high". This is an advantage for the treatment of central nervous system diseases, but for the treatment of pancreatic cancer, high BBB penetrability may bring potential neurotoxicity risks, which needs to be focused on by subsequent toxicology research. In addition, hERG inhibition is predicted as' no ', indicating a lower risk of inducing QT interval prolongation and arrhythmia in the heart, which is a favorable safety signal. However, the Ames test result was 1.8, indicating that the compound exhibited a certain degree of mutagenicity in bacterial reverse mutation assays, suggesting a potential genetic toxicity risk that needs to be rigorously evaluated in preclinical safety assessments.
Plant sources and extraction methods
6- (5,6-dihydroquercetin) diamine is not a naturally occurring plant secondary metabolite, but a semi synthetic derivative obtained by structural modification of the natural product quercetin. Therefore, its "plant source" should be understood as the plant source of the starting material, baicalein. White Quercetin is mainly distributed in Papaveraceae plants, such as white Quercetin（Chelidonium majus）Bo Luohui（Macleaya cordata）Blood water grass（Eomecon chionantha）Bald sores flower（Dicranostigma leptopodum）And swallow grass（Corydalis Spp.), etc. Among them, Baiqucai and Boluohui are the main raw materials for industrial extraction of Baiqucai red alkaloid.
The traditional methods for extracting red alkaloid from Bai Qu Cai usually include solvent extraction, acid water extraction, and alcohol extraction. Taking the whole plant of Baiqu Cai as an example, ethanol or methanol is commonly used for reflux extraction. After concentration, the extract is acidified with dilute acid (such as hydrochloric acid) to make the alkaloids salt and dissolve in the aqueous phase. Then, alkalization (such as ammonia water) is used to free the alkaloids, followed by extraction with organic solvents (such as chloroform, ethyl acetate). Finally, the Baiqu Cai red alkaloid monomer is separated and purified by column chromatography (such as silica gel column, alumina column).
After obtaining quercetin, the synthesis of 6- (5,6-dihydroquercetin) diamine is usually carried out by chemical synthesis. The key steps include: firstly, reducing the C5-C6 double bond of quercetin to obtain 5,6-dihydroquercetin; Then, through nucleophilic substitution reaction, two 5,6-dihydroquercetin units are connected to an amino donor (such as ammonia or ammonium salt). The specific reaction conditions (such as temperature, solvent, catalyst, reaction time) and purification methods (such as recrystallization, preparative high-performance liquid chromatography) determine the yield and purity of the final product. Due to the complex structure of the compound, strict control of reaction conditions is required during the synthesis process to avoid the occurrence of side reactions.
Pharmacological activity research
At present, the research on the pharmacological activity of 6- (5,6-dihydrochelerythrin) diamine is still in the early stage of exploration, but the existing preliminary research results have shown its great potential in anti pancreatic cancer. Its pharmacological activity is mainly reflected in the following aspects:
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Inhibition of pancreatic cancer cell proliferation: Cell viability tests in vitro (such as MTT method, CCK-8 method) showed that the compound showed significant inhibitory effect on proliferation of a variety of pancreatic cancer cell lines (such as PANC-1, MIA PaCa-2, BxPC-3). Its half maximal inhibitory concentration (IC50) is usually in the micromolar range, and its toxicity to normal pancreatic ductal epithelial cells (such as hTERT HPNE) is relatively low, demonstrating a certain degree of selectivity. This selective killing effect is an important foundation for its development as an anti-tumor drug.
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Inducing cell apoptosis Flow cytometry and Western blot analysis confirmed that the compound can induce apoptosis of pancreatic cancer cells in a dose and time-dependent manner. Specifically, it is manifested by increasing the proportion of apoptotic cells, activating Caspase-3/9, upregulating the expression of pro apoptotic proteins Bax and Bad, and downregulating the expression of anti apoptotic protein BCL2. This indicates that it exerts a pro apoptotic effect through the mitochondrial pathway (endogenous apoptotic pathway).
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Inhibit cell migration and invasion Scratch test and Transwell chamber test showed that the compound could significantly inhibit the migration and invasion of pancreatic cancer cells. This is closely related to the downregulation of matrix metalloproteinase MMP2 expression, which is a key enzyme in degrading extracellular matrix and promoting tumor metastasis. In addition, inhibition of HIF1A may also suppress metastasis by affecting the epithelial mesenchymal transition (EMT) process.
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Reverse multidrug resistance The inherent resistance of pancreatic cancer to chemotherapy drugs (such as gemcitabine) is one of the main reasons for treatment failure. Preliminary studies have shown that this compound can effectively reverse multidrug resistance mediated by ABCB1 (P-glycoprotein). ABCB1 is a drug efflux pump, and its overexpression is a key mechanism leading to a decrease in intracellular concentration and efficacy of chemotherapy drugs. This compound may increase the sensitivity of drug-resistant cells to chemotherapy drugs by directly inhibiting the activity of ABCB1 or downregulating its expression level.
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Regulating the tumor microenvironment By targeting the TLR4 and STAT3 signaling pathways, this compound may affect the inflammatory response and immunosuppressive state in the tumor microenvironment. The activation of TLR4 can promote the release of inflammatory factors, while the sustained activation of STAT3 is associated with tumor immune escape. Inhibiting these pathways helps reshape the tumor microenvironment and enhance anti-tumor immune response.
Mechanism of action and molecular targets
The mechanism of action of 6- (5,6-dihydrocheleryl) diamine reflects the network regulation characteristics of "multiple targets, multiple pathways", which is highly consistent with the complex molecular pathology of pancreatic cancer. The core mechanism of its action can be summarized as the regulation of the following key signal networks:
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Apoptotic signaling network This compound directly acts on BCL2 family proteins. As an anti apoptotic protein, BCL2 is often overexpressed in pancreatic cancer, which is an important guarantee for tumor cell survival. This compound disrupts the integrity of the mitochondrial outer membrane by downregulating BCL2 and upregulating Bax, leading to the release of cytochrome c and activating the Caspase cascade reaction, ultimately executing the apoptotic program. Meanwhile, inhibition of STAT3 indirectly weakens the transcriptional activation of BCL2, forming a positive feedback amplification effect.
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Inflammation and immune signaling network The TLR4/STAT3 axis is a key bridge connecting inflammation and tumors. After TLR4 recognizes damage associated molecular patterns (DAMPs) or pathogen associated molecular patterns (PAMPs), it activates downstream NF - κ B and STAT3 signaling, promoting the production of inflammatory factors (such as IL-6, TNF - α) and immunosuppressive factors (such as IL-10, TGF - β). This compound blocks this vicious cycle by inhibiting the phosphorylation of TLR4 and STAT3, thereby suppressing tumor associated inflammation and potentially restoring anti-tumor immune surveillance function.
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Drug resistance and metastasis signaling network ABCB1 and MMP2 are key executors of tumor drug resistance and metastasis. The high expression of ABCB1 is one of the core mechanisms of chemotherapy resistance. This compound inhibits the function or expression of ABCB1 by directly binding or regulating transcription factors such as NF - κ B and STAT3, thereby increasing the accumulation of chemotherapy drugs in cells. The inhibition of MMP2 directly weakens the ability of tumor cells to degrade extracellular matrix, invade blood vessels and lymphatic vessels. In addition, the regulation of PRKCA may also affect the cytoskeleton rearrangement and migration ability.
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Stress adaptation signal network The survival of tumor cells in hypoxic and oxidative stress environments depends on the adaptive regulation of HIF1A and NFE2L2. HIF1A is a core transcription factor in hypoxia response, driving angiogenesis (such as VEGF), glycolysis, and EMT. NFE2L2 is the main regulator of antioxidant stress, protecting cells from damage caused by reactive oxygen species (ROS). The inhibition of these two targets by this compound may disrupt the stress adaptation mechanism of tumor cells, making them more susceptible to attacks from chemotherapy drugs and microenvironmental stress.
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Other potential targets TRPV1 is a non selective cation channel that plays an important role in pain perception and inflammation. Its expression and function in pancreatic cancer are not completely clear, but it may participate in the neuro immune interaction in the tumor microenvironment. TOP1 is DNA topoisomerase, a classic target of camptothecin chemotherapy drugs. The inhibitory activity of this compound on TOP1 suggests that it may have a direct DNA damaging effect, but its specific mechanism needs further verification.
To sum up, this compound forms a synergistic network by simultaneously acting on multiple key nodes such as apoptosis, inflammation, drug resistance, metastasis, stress adaptation, etc., so as to achieve comprehensive inhibition of pancreatic cancer cells. This multi-target mode of action is the potential advantage of overcoming single target drug resistance and improving treatment efficacy.
Evaluation of drug properties and pharmacokinetics
The evaluation of drug properties is a key link connecting lead compounds with clinical candidate drugs. Based on existing data, the pharmacological properties of 6- (5,6-dihydroquercetin) diamine exhibit a combination of opportunities and challenges.
Advantage aspects：
* Multi-target activity As mentioned above, its multi target action mode meets the treatment needs of complex diseases (such as pancreatic cancer), which is expected to achieve "one drug with multiple effects" and reduce the probability of drug resistance.
* Good hERG safety Predicting no hERG inhibition risk reduces the potential risk of cardiac toxicity.
* High lipid solubility A high LogP value is beneficial for its penetration into the cell membrane, entry into intracellular targets, and possible absorption through the lymphatic system, improving oral bioavailability.
Challenge aspect：
* Extremely poor water solubility The water solubility of 0.0000 is the biggest obstacle to drug development. Extremely low water solubility will lead to poor oral absorption, low bioavailability, uneven distribution in the body, and difficulty in injection administration. Improvement must be achieved through formulation techniques such as nanocrystals, liposomes, phospholipid complexes, cyclodextrin inclusion complexes, or prodrug design by introducing water-soluble groups such as phosphate esters and amino acid esters.
* Potential genetic toxicity A positive Ames test result suggests that it may have mutagenicity, which is a significant risk in drug development. A more comprehensive genetic toxicity assessment (such as in vivo micronucleus test, chromosome aberration test) is needed, and the structure toxicity relationship should be explored to reduce toxicity through structural modification.
* High blood-brain barrier penetrability Although it is an advantage for some indications, high BBB penetrability may lead to adverse reactions of the central nervous system for pancreatic cancer treatment, such as dizziness, lethargy, and even neurotoxicity. It is necessary to design a delivery system targeting the pancreas or reduce BBB penetration through structural modifications.
* Pharmacokinetic properties unknown Currently, there is a lack of systematic research on the absorption, distribution, metabolism, and excretion (ADME) of this compound. Its high LogP value suggests that it may have high protein binding rate, long half-life, and extensive metabolism (such as CYP450 enzyme mediated oxidative metabolism). In vivo pharmacokinetic experiments are required to clarify key parameters such as metabolic stability, metabolites, and excretion pathways.
Pharmacokinetic prediction Based on its physicochemical properties, its pharmacokinetic characteristics can be preliminarily predicted: oral absorption may be poor, and bioavailability may be low; After intravenous injection, due to high lipid solubility, it may rapidly distribute to lipid rich tissues such as liver, fat, and brain; Metabolism may mainly occur in the liver, through enzyme systems such as CYP3A4; Excretion may occur in the form of metabolites through bile and feces, and the amount of prototype drug excreted through the kidneys is extremely small.
Clinical application prospects and prospects
Although the research and development of 6- (5,6-dihydrocheleryl) diamine is still in its early stage, its unique chemical structure and multi-target mechanism of action endow it with broad application prospects in the treatment of pancreatic cancer.
Potential clinical application directions：
1. Monotherapy: For certain specific molecular subtypes of pancreatic cancer (such as BCL2 overexpression, STAT3 activation), this compound may directly play an anti-tumor role as a single drug therapy.
2. combination therapy Given its potential to reverse multidrug resistance, the most likely application prospect is to use it in combination with existing chemotherapy drugs (such as gemcitabine, paclitaxel, oxaliplatin, irinotecan) as a chemotherapy sensitizer to overcome resistance and improve chemotherapy efficacy. For example, combination with gemcitabine may significantly improve the killing effect on gemcitabine resistant pancreatic cancer cells.
3. Targeting the tumor microenvironment By inhibiting the TLR4/STAT3 axis, this compound may act as an immunomodulatory agent and be used in combination with immune checkpoint inhibitors (such as PD-1/PD-L1 antibodies) to reshape the immunosuppressive tumor microenvironment and enhance the efficacy of immunotherapy.
4. Nano drug delivery system In view of its poor water solubility and potential toxicity, the development of nano delivery systems targeting pancreatic cancer (such as liposomes, polymer micelles, mesoporous silica nanoparticles) is the focus of future transformation research. By modifying ligands on the surface (such as antibodies or peptides targeting EGFR, uPAR, CA19-9), drug enrichment at the tumor site can be achieved, improving efficacy and reducing systemic toxicity.
Future research directions：
1. structural optimization Based on its binding mode with the target, structural modification was carried out through computer-aided drug design (CADD) with the aim of improving water solubility, reducing genetic toxicity, and optimizing target selectivity. For example, introducing polar groups on the amino bridge or modifying the core of dihydroquercetin.
2. In depth mechanism research Using cutting-edge techniques such as CRISPR-Cas9 gene editing, proteomics, and metabolomics, comprehensively analyze its multi-target action network, clarify its key targets and signaling pathways, and provide a basis for precision therapy.
3. Pharmacokinetic and toxicological studies of the system Conduct in vitro and in vivo ADME experiments to evaluate its metabolic stability, metabolites, tissue distribution, and excretion pathways. At the same time, conduct comprehensive toxicological evaluations on acute and chronic toxicity, reproductive toxicity, genetic toxicity, etc., and clarify their safety window.
4. Preclinical pharmacodynamic evaluation The xenotransplantation model (PDX model) and genetic engineering mouse model (GEMM) from pancreatic cancer patients were used to evaluate their anti-tumor activity in vivo, the effect of combined drugs and the impact on tumor microenvironment.
5. Formulation development Focus on developing formulations that can solve the problems of poor water solubility and targeted delivery, such as pH responsive nanoparticles, liposomes, prodrug nano assemblies, etc.
Conclusion
6- (5,6-dihydrocheleryl) diamine, as a novel dimer derivative derived from the natural product chelerythrine, shows unique value in the field of anti pancreatic cancer drug research and development by virtue of its unique chemical structure and multi-target mechanism of action. By simultaneously regulating multiple key targets such as BCL2, TLR4, STAT3, ABCB1, MMP2, and HIF1A, it is expected to overcome the core challenges of drug resistance, metastasis, and immune escape in the treatment of pancreatic cancer.
However, the challenges faced by its medicinal properties cannot be ignored, especially the extremely poor water solubility, potential genetic toxicity, and safety risks caused by high blood-brain barrier penetration. Future research should focus on overcoming these obstacles through structural optimization and advanced formulation technologies, and conducting systematic and in-depth pharmacokinetic, toxicological, and pharmacodynamic studies.
In a word, 6- (5,6-dihydrocheleryl) diamine is a potential lead compound, which provides a new chemical entity and idea for the development of new treatment strategies for pancreatic cancer, the "king of cancer". Although the road from laboratory to clinical is still long and full of challenges, its in-depth research and development is expected to bring new hope to patients suffering from pancreatic cancer.
![Bis[6-(5,6-dihydrochelerythrinyl)]amine](/upload/0201/05/165393-48-6.png)
