Chizhi acid C: research progress on anti-tumor natural products derived from Ganoderma lucidum
1. Overview
Lucideng acid C (CAS number: 95311-96-9) is a traditional medicinal fungus derived from Ganoderma lucidum（Ganoderma lucidum）Natural triterpenoid compounds isolated from the middle. As one of the important bioactive components in Ganoderma lucidum, gibberellic acid C has attracted widespread attention in the field of natural product pharmacy due to its significant anti-tumor activity. Modern pharmacological studies have shown that this compound can effectively inhibit PMA induced matrix metalloproteinase-9 (MMP-9) activity and exhibit significant anti invasive effects on liver cancer cells such as HepG2 cells. In addition, bioinformatics analysis suggests that gibberellic acid C may exert its pharmacological effects by regulating multiple key tumor related targets (such as BCL2, TP53, CDKN2A, PTEN, MYC), especially in association studies with hematological tumors such as lymphoma, showing potential value. With the deepening of research on the active ingredients of Ganoderma lucidum, gibberellic acid C, as a compound with clear structure and significant activity, has become one of the important candidate molecules for the study of anti-tumor drug lead compounds. This article will systematically review the research status of Ganoderma lucidum acid C from its chemical structure, plant origin, pharmacological mechanism, medicinal evaluation, and research prospects.
2. Chemical structure and physicochemical properties
The molecular formula of gibberellic acid C is C ₂₇ H ₄₀ O ₇, with a molecular weight of 476.6100 g/mol, belonging to highly oxidized lanostane type triterpenoids. The SMILES structural formula is: C C@H[C@H]1CC(=O)[C@@]2(C)C3=C(C(=O)C@@H[C@]12C)[C@@]1(C)CCC@H C(C)(C)[C@H]1C[C@@H]3O， Displaying multiple chiral centers and oxygen-containing functional groups (including carboxyl, ketone, and hydroxyl groups), these structural features are closely related to their biological activity and physicochemical properties.
From the perspective of pharmacological parameters, the lipid water partition coefficient (LogP) of red sesame acid C is 2.3858, indicating its lipophilicity, but still within the ideal range (LogP is generally considered to be between 1-3, which is more suitable for oral absorption). Its topological polar surface area (TPSA) is 132.13 Å ², slightly higher than the commonly considered good membrane permeability threshold (below approximately 140 Å ²), indicating that it may have moderate membrane permeability. The water solubility is 0.1165 mg/mL, which belongs to the slightly soluble level, which may affect its formulation development and in vivo bioavailability. The permeability value of Caco-2 cells is 3.2056, indicating that its intestinal absorption potential is still acceptable. However, the blood-brain barrier (BBB) permeability has been evaluated as "low", indicating that it is difficult to enter the central nervous system. This is not a fatal disadvantage for anti-tumor drugs that mainly act on the peripheral system. The plasma protein binding rate (PPB) is as high as 85.67%, which means that most of it binds to proteins in the bloodstream, which may affect its free drug concentration and efficacy. Preliminary toxicological assessment shows that its Ames test, chromosomal aberration, hERG inhibition, etc. are all negative or "none", indicating a low risk of genetic and cardiac toxicity. However, the Ser_LK (serum alkaline phosphatase) index is "yes", suggesting that attention may need to be paid to its impact on liver function. Overall, the physicochemical properties of Ganoderma lucidum acid C basically conform to the Lipinski five rules (molecular weight<500, LogP<5, number of hydrogen bond donors<5, number of hydrogen bond acceptors<10), and have the basis to become a lead compound for oral drugs. However, solubility and protein binding rate need to be optimized.
3. Plant sources and traditional applications
Chizhi acid C comes from Ganoderma lucidum（Ganoderma lucidum）Also known as Chizhi or Ruicao, it belongs to the Basidiomycota phylum and Lingzhi family. Lingzhi has a medicinal history of over two thousand years in East Asia, especially in China, Japan, and South Korea, and is known as the "immortal herb" or "elixir of life". In the "Shennong Bencao Jing", Ganoderma lucidum is listed as a top-grade herb, which is recorded as "mainly used for hearing loss, joint benefit, protecting the spirit, nourishing essence and qi, strengthening muscles and bones, and having good color". Traditional Chinese medicine believes that Ganoderma lucidum has a calm nature, sweet taste, and can regulate the heart, lungs, liver, and kidney meridians. It has the effects of tonifying qi and calming the mind, stopping cough and asthma, and is commonly used to treat symptoms such as weakness, insomnia, palpitations, coughing, wheezing, and excessive phlegm.
Modern pharmacognostic research has shown that the medicinal parts of Ganoderma lucidum are mainly fruiting bodies and mycelium, and its active ingredients include polysaccharides, triterpenoids, sterols, proteins, etc. Among them, triterpenoids are important secondary metabolites in Ganoderma lucidum, with various pharmacological activities such as anti-tumor, anti-inflammatory, hepatoprotective, and antiviral effects. Chizhi acid C is an important member of the triterpenoid family in Ganoderma lucidum, usually isolated from lipid soluble extracts of Ganoderma lucidum fruiting bodies. With the advancement of separation and purification techniques and structural identification methods, more than 200 triterpenoid compounds have been identified from Ganoderma lucidum. Gibberellic acid C has become a research hotspot due to its unique structure and significant cytotoxicity. Although traditional applications have not directly targeted gibberellic acid C, the anti-tumor and immune regulatory effects of Ganoderma lucidum extract as a whole provide historical basis and material basis for the in-depth study of its monomeric compounds.
4. Pharmacological activity and mechanism of action
The most notable pharmacological activity of Ganoderma lucidum acid C is its anti-tumor effect, especially its anti invasion and anti metastasis effects. Research has shown that quercetin C can significantly inhibit MMP-9 activity induced by PMA (a tumor promoter). MMP-9 (matrix metalloproteinase-9) belongs to the zinc dependent endopeptidase family and can degrade the main components of extracellular matrix (ECM) and basement membrane (such as type IV collagen), playing a crucial role in tumor invasion and metastasis. By inhibiting the activity of MMP-9, quercetin C can effectively reduce the invasive ability of HepG2 liver cancer cells, providing direct evidence for its anti-tumor metastasis.
Further research on the mechanism of action revealed multiple key signaling pathways and molecular targets that may be regulated by gibberellic acid C through target prediction and experimental verification
- BCL2 BCL2 is an important anti apoptotic protein that is overexpressed in various tumors and promotes cell survival. Chizhi acid C may promote tumor cell apoptosis by downregulating the expression of BCL2 or interfering with its function.
- TP53 The p53 protein encoded by the TP53 gene is a classic tumor suppressor that participates in cell cycle arrest, DNA repair, and apoptosis. Chizhi acid C may restore its anti-cancer function in tumor cells by stabilizing p53 protein or enhancing its transcriptional activity.
- CDKN2A This gene encodes the p16INK4a protein, which is an inhibitor of cyclin dependent kinase (CDK) and negatively regulates the cell cycle progression. Chizhi acid C may induce cell cycle arrest by upregulating CDKN2A expression.
- PTEN PTEN is an important phosphatase that inhibits cell growth and survival by antagonizing the PI3K/AKT signaling pathway. Chizhi acid C may inhibit tumor cell proliferation by activating PTEN and suppressing AKT activation.
- MYC MYC is a proto oncogene that regulates various cellular processes, including proliferation, metabolism, and apoptosis. Chizhi acid C may inhibit the transcription or expression of MYC, blocking its pro tumor effect.
These targets do not act in isolation, but form a complex regulatory network. For example, p53 can transcriptionally activate PTEN and CDKN2A, while inhibiting BCL2 and MYC; PTEN indirectly affects the stability of MYC by inhibiting the PI3K/AKT pathway. Chizhi acid C may act on multiple nodes simultaneously, synergistically exerting anti-tumor effects. Of particular note, these targets play important roles in the occurrence and development of lymphoma: BCL2 overexpression is common in follicular lymphoma; TP53 mutations are associated with lymphoma progression and drug resistance; CDKN2A deficiency is found in various subtypes of lymphoma; PTEN inactivation can promote the survival of lymphoma cells; MYC abnormal activation is a hallmark of Burkitt's lymphoma and other conditions. Therefore, through multi-target intervention, gibberellic acid C is expected to have therapeutic effects on hematological tumors such as lymphoma, providing a theoretical basis for its further development as an anti lymphoma drug.
In addition to its direct anti-tumor effect, gibberellic acid C may also indirectly inhibit the tumor microenvironment through anti-inflammatory and antioxidant pathways. For example, inhibition of MMP-9 not only affects invasion, but also regulates inflammatory cell infiltration and angiogenesis. However, most of the current mechanism research is still at the cellular and molecular level, with a relative lack of animal models and preclinical studies, and further in-depth validation is needed.
5. Evaluation of drug properties
Based on the provided pharmacological parameters, we can conduct a preliminary assessment of the potential of Gibberellic Acid C as a drug:
Firstly, according to Lipinski's Five Rules(Usually used to predict oral bioavailability):
1. The molecular weight (MW) is 476.61 g/mol, slightly below the upper limit of 500, which is consistent.
2. The LogP value is 2.3858, between 1-3, which is within the ideal range and meets the requirements.
3. The number of hydrogen bond donors (structurally containing multiple hydroxyl and carboxyl groups, but the number may be controlled within 5) needs to be accurately calculated, but preliminary judgments may be close or consistent.
4. The number of hydrogen bond acceptors (7 oxygen atoms, which may form multiple hydrogen bond sites) may be close to the upper limit of 10, but it may still meet the criteria.
Overall, red sesame acid C basically meets the Lipinski rule, indicating its good oral absorption potential.
Other key parameter analysis:
- Solubility and permeability Low water solubility (0.1165 mg/mL) may affect its dissolution and absorption. Caco-2 permeability (3.2056) is acceptable, but BBB permeability is low, indicating that it is not easy to enter the brain and may not be a problem for treating peripheral tumors, but it also limits its application in brain tumors.
- protein binding High plasma protein binding rate (85.67%) may lead to low free drug concentration, requiring higher doses to achieve effective blood drug concentration, and may also affect drug distribution and clearance.
- Toxicity risk The Ames test is negative, with no chromosomal abnormalities or hERG inhibition, indicating a low risk of genetic and cardiac toxicity and good safety. However, a positive Ser_LK suggests that it may have an impact on liver function and further evaluation is needed in animal toxicology experiments.
- Metabolic stability The Peff (effective permeability coefficient) is 1.4235, and the SyneAccessibility (synthetic accessibility) is 5.0566, indicating that its synthesis and modification have certain feasibility.
Overall, as a natural product lead compound, red sesame acid C has a certain medicinal basis, especially in terms of anti-tumor activity, with significant advantages. but its Main challenges Due to: ① poor water solubility, which may affect formulation development and bioavailability; ② High protein binding rate may reduce drug efficacy; ③ Further validation of its in vivo efficacy and toxicity is needed. Future structural optimization can focus on improving solubility (such as making salts or prodrugs), reducing protein binding, and enhancing targeting.
6. Research Status and Application Prospects
At present, the research on red sesame acid C is still in progress Preclinical stage Mainly focused on the following aspects:
1. Activity screening and mechanism exploration Most studies have validated its anti proliferative, anti invasive, and pro apoptotic activities through cell models, and explored its targets and pathways through molecular docking, gene knockout/overexpression, and other techniques.
2. Research on structural analogues There are also various gibberellic acid analogues (such as gibberellic acid A, B, D, etc.) in Ganoderma lucidum, some of which have similar or stronger activities. Structure activity relationship studies can help discover better candidate molecules.
3. Combination therapy research There are studies attempting to combine gibberellic acid C with conventional chemotherapy drugs such as cisplatin and doxorubicin to observe whether it has a synergistic effect or reversal of drug resistance.
Despite its broad prospects, the clinical application of red sesame acid C still faces many challenges:
- Insufficient validation of in vivo pharmacodynamics At present, there is a lack of systematic animal model data (especially transplant tumor models), which makes it difficult to accurately evaluate their in vivo anti-tumor effects and dose relationships.
- Blank space in pharmacokinetic research Its absorption, distribution, metabolism, and excretion (ADME) characteristics are not yet clear, which is a key step in advancing preclinical research.
- Difficulties in formulation development The problem of low solubility requires appropriate formulation techniques (such as nano formulations, liposomes, cyclodextrin inclusion complexes, etc.) to solve.
- Synthesis and Supply Although it can be extracted from Ganoderma lucidum, the yield is low, the cost is high, and fully synthetic or semi synthetic routes need to be developed to achieve large-scale supply.
Future research directions may include:
1. In depth mechanism research Using CRISPR screening, proteomics and other technologies, comprehensively elucidate its multi-target action network and cell fate determination mechanism.
2. Structural modification and optimization By chemical synthesis or biotransformation, a series of derivatives are prepared and their pharmacological parameters are optimized (such as increasing solubility, reducing protein binding, and enhancing targeting).
3. Preclinical development Establish a reliable animal model, complete the evaluation of drug efficacy, pharmacokinetics, and toxicology, and provide data support for its application for clinical research.
4. Explore new indications In addition to lymphoma, its target spectrum suggests that it may also have potential effects on many solid tumors, such as liver cancer, breast cancer, colorectal cancer, and so on, which is worth expanding research.
In summary, as an active triterpenoid component in Ganoderma lucidum, red sesame acid C is expected to develop into a novel anti-tumor candidate drug due to its multi-target anti-tumor mechanism and good pharmacological basis. With the cross fusion of natural product chemistry, pharmacology, and medicinal chemistry, the research on gibberellic acid C and its derivatives will provide new ideas and weapons for tumor treatment. However, the road from laboratory to clinical is still long and requires the collaboration and continuous investment of multidisciplinary teams.
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