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Caged Polyprenylated Xanthones in Garcinia hanburyi and the Biological Activities of Them
Authors He R, Jia B , Peng D, Chen W
Received 20 June 2023
Accepted for publication 2 November 2023
Published 5 December 2023 Volume 2023:17 Pages 3625—3660
DOI https://doi.org/10.2147/DDDT.S426685
Checked for plagiarism Yes
Review by Single anonymous peer review
Peer reviewer comments 2
Editor who approved publication: Prof. Dr. Tin Wui Wong
Ruixi He, Buyun Jia, Daiyin Peng, Weidong Chen
School of Pharmacy, Anhui University of Chinese Medicine, Hefei, People’s Republic of China
Correspondence: Ruixi He, School of Pharmacy, Anhui University of Chinese Medicine, No. 350 Longzihu Road, Xinzhan District, Hefei, 230012, People’s Republic of China, Tel +8613637080511, Fax +8655168129099, Email [email protected]
Abstract: The previous phytochemical analyses of Garcinia hanburyi revealed that the main structural characteristic associated with its biological activity is the caged polyprenylated xanthones with a unique 4-oxatricyclo [4.3.1.03,7] dec-2-one scaffold, which contains a highly substituted tetrahydrofuran ring with three quaternary carbons. Based on the progress in research of the chemical constituents, pharmacological effects and modification methods of the caged polyprenylated xanthones, this paper presents a preliminary predictive analysis of their drug-like properties based on the absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties. It was found out that these compounds have very similar pharmacokinetic properties because they possess the same caged xanthone structure, the 9,10-double bond in a,b-unsaturated ketones are critical for the antitumor activity. The author believes that there is an urgent need to seek new breakthroughs in the study of these caged polyprenylated xanthones. Thus, the research on the route of administration, therapeutic effect, structural modification and development of such active ingredients is of great interest. It is hoped that this paper will provide ideas for researchers to develop and utilize the active ingredients derived from natural products.
Keywords: caged polyprenylated xanthones, pharmacological effects, antitumor, modification, ADME/T properties
Graphical Abstract:
Introduction
Garcinia hanburyi is widely distributed in the tropical rainforests of Southeast Asia. Gamboge is the dried resin exuded from the stems of Garcinia hanburyi that can be used as a pigment and has also been used for a long time as a folk medicine.1 In China, people are increasingly concerned about the safety of toxic herbs. Garcinia hanburyi is regulated as a toxic drug for medical use, and it requires special modification for clinical use. The previous phytochemical analyses of Garcinia hanburyi revealed that the main structural characteristic associated with its biological activity is the caged polyprenylated xanthones with a specialized 4-oxatricyclo [4.3.1.03,7] dec-2-one scaffold,2–9 which contains a highly substituted tetrahydrofuran ring.10 We have compiled the relevant literature and found out that more than 50 different xanthones have now been extracted from gamboge. The available evidence suggests that gamboge has anticancer properties, with gambogenic acid (GNA) and gambogic acid (GA) being the main components responsible for these activities. They have been demonstrated to exert cytotoxic activities through a variety of mechanisms.11–14 Among them, GA has been applied to treat a wide range of cancers, such as breast, liver, gastric, lung, colon, and skin cancers. Its therapeutic effects have been well established,15 and it has been shown to exert anticancer effects through apoptosis induction, cell cycle arrest, telomerase and angiogenesis inhibition.16,17 In recent years, increasing evidence has demonstrated that GNA exhibits higher antitumor activity and lower toxicity compared to GA, and the extraction process is simple and less costly.18–21 Despite these advantages, GNA has not been approved for clinical application mainly due to its poor aqueous solubility and low bioavailability.22 With the aim of overcoming these limitations, researchers have carried out various studies such as on the technology nanocarrier drug delivery, to improve the bioavailability of GNA.
Due to the diversity and potent activities of caged polyprenylated xanthones extracted from Garcinia hanburyi, a series of in-depth studies have been conducted by researchers all over the world. Our team has conducted study on these bioactive ingredients. Our work covers many aspects, including compound isolation, pharmacokinetics, and formulation. In our previous studies, several highly fascinating methods were found to improve the therapeutic efficacy of GNA, including the use of solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs),23 liquid crystal dispersions,24 PEGylated liposomes, PEGylated nonionic surfactant vesicles,25 and folic acid-modified nonionic surfactant vesicles.26 More than 50 different types of caged polyprenylated xanthones have been extracted from Garcinia hanburyi, but researchers have mostly focused more on GNA and GA. However, the basic properties of the other ingredients, particularly their absorption, distribution, metabolism, excretion and toxicity (ADME/T) properties, all of which are the key factors affecting the efficacy of drugs in vivo, are unclear. However, in the development of new drugs, the evaluation of the physicochemical properties, such as ADME/T properties, is limited by a number of factors, such as the high economic cost and the long time required. Therefore, these properties are usually considered at the stage of clinical research. According to statistics, 40% of drug candidates are eliminated from further development due to poor bioavailability, pharmacokinetic properties or toxicity.27 Based on a collection of reliable experimental data as reported, a computer program was developed to effectively predict the ADME/T properties of bioactive ingredients.28 Compared with the traditional experiments in vivo, computer programs can process multiple active ingredients in batches and predict their ADME/T properties by simply providing the structure of the compound, thus making this process more efficient and less costly.29 PkCSM software is a distance-based graphical feature that can be used to predict and optimize the pharmacokinetic properties and toxicity of small molecules. It consists of 30 predictors divided into five major classes: absorption (7 predictors), distribution (4 predictors), metabolism (7 predictors), excretion (2 predictors), and toxicity (10 predictors).30 To start forecasting, only with the SMILES code of the compound, it enables easy and rapid early stage assessment of compounds. Under the pkCSM program, the ADME/T properties of 51 caged polyprenylated xanthones derived from Garcinia hanburyi were predicted and summarized. It is hoped that this will promote the development and utilization of natural products.
Chemical Structures of the Xanthones in Garcinia hanburyi
To predict and compare the ADME/T properties of the caged polyprenylated xanthones derived from Garcinia hanburyi more comprehensively, we summarized 51 of them that had been isolated to date. The caged polyprenylated xanthones currently known derived from Garcinia hanburyi are listed in Table 1. As typical caged polyprenylated xanthones in Garcinia hanburyi, GA (Compound 9) and GNA (Compound 36) are of great interest for their proliferation inhibitory effects on a variety of tumor cells.
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Table 1 Chemical Structures of the Caged Polyprenylated Xanthones Derived from Garcinia hanburyi |
The Role of Caged Polyprenylated Xanthones in Diseases
Antitumor
In recent years, in vitro and in vivo experiments have shown that the caged polyprenylated xanthones extracted from Garcinia hanburyi exhibits anti-tumor effects, the anti-tumor effects of GA and GNA are mainly achieved through induction of apoptosis, cell cycle arrest and inhibition of tumor cell invasion and migration, and the compounds of gambogefic acid, 7-methoxygambogellic acid, 7-methoxygambogic acid, 7-methoxyepigambogic acid, 8,8a-dihydro-8-hydroxymorellic acid, 8,8a-dihydro-8-hydroxygambogenic acid, oxygambogic acid, gambogenific acid, 7-methoxyisomorellinol, 8,8a-dihydro-8-hydroxygambogic acid also have inhibitory effects on cancer cells.4
Induction of Apoptosis
It was demonstrated that GA induces apoptosis in non-small cell lung cancer (NSCLC) A549 cells by upregulating the expression of pro-apoptotic genes BAX and PUMA and downregulating the expression of anti-apoptotic gene BCL-2 through transcription factor P53.35 In addition, GA can increase the sensitivity of MCF-7 to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and promoted TRAIL-induced apoptosis in breast cancer cells by enhancing the activity of caspase-3 and caspase-8.36 GA can also induce apoptosis in glioblastoma by increasing the levels of the pro-apoptotic proteins BAX and apoptosis-inducing factor (AIF), and this is a non-caspase-related apoptotic pathway.37,38 The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling pathway are closely related to tumor cell apoptosis, and it was shown that GA could induce apoptosis of esophageal cancer cells by inhibiting the JAK-STAT signaling pathway.39 The mechanism of GNA-induced apoptosis in tumor cells has also received considerable attention in recent years, studies have shown that GNA can induce apoptosis in breast cancer cells through the mitochondrial pathway, it can also induce apoptosis by inhibiting the expression of the anti-apoptotic protein BCL-2 and activating apoptosis-related proteins.40,41
Blocking the Cell Cycle
Cell cycle factor is an important target for tumor treatment. Several studies show that caged polyprenylated xanthones in Garcinia hanburyi can block the tumor cell cycle. GNA can induce apoptosis by downregulating the expression of cyclin-dependent kinases (CDKs) that arrest the cell cycle in the G1 phase and subsequently activate caspases.42 GA can induce mRNA expression of genes related to cell cycle arrest, thereby causing cells to arrest in the G0/G1 phase.43
Inhibit the Invasion and Metastasis of Tumor Cells
Invasion and metastasis of tumor cells are the main reasons for the poor prognosis of patients. Experimental results have shown that GA can reduce the invasion of breast cancer cells and colon cancer cells, follow-up mechanistic studies revealed that this may be related to the c-Jun N-terminal kinase (JNK) signaling pathway, which increases the secretion of matrix metalloproteinases (MMPs) in cancer cells, disrupts the extracellular matrix, decreases intercellular adhesion, and thus promotes invasion and metastasis of cancer cells.44 GNA and isomorellin were found to attenuate the migration and invasion of tumor cells by inhibiting the NF-κB pathway.45,46
Inhibit Angiogenesis
It was revealed that GNA could significantly reduce p-PI3K, p-AKT, and vascular endothelial growth factor (VEGF) expression, further experiments showed that GNA inhibits angiogenesis through the PTENPI3K/AKT/VEGF/eNOS pathway.47 In addition, it was also demonstrated that morellic acid, gambogenin and isogambogenic acid showed comparable antiangiogenic activities with less toxicities than GA.48
Induction of Cellular Autophagy
In recent years, autophagy has received extensive attention in numerous researches of antitumor drugs. GA could induce significant upregulation the expression of autophagy-related factors ATG7, BECLIN-1 and LC3-II in acute lymphoid leukemia cells, while inhibiting Wnt/β-catenin signaling, thus further inhibiting cell growth.49 It was observed that glioma cells treated with GNA showed increased expression of autophagic proteins and increased secretion of autophagic vesicles, suggesting that GNA can induce autophagy in tumor cells, thereby inhibiting tumor growth.50
Other Mechanism Studies
The accumulation of reactive oxygen species (ROS) has an important impact on the development of tumors. It was suggested that GA can induce the accumulation of ROS in tumor cells, which may be related to the ability of GA to inhibit cytosolic thioredoxin (TRX-1) and mitochondrial thioredoxin (TRX2) distributed in the cytoplasm and mitochondrion, which play a key role in maintaining ROS homeostasis.51–53 Recent studies have observed that GA kills cancer cells by inducing a vacuolization-associated cell death, and this phenomenon may be associated with GA-induced proteasomal inhibition leads to the endoplasmic reticulum (ER) dilation and ER stress in treated cancer cells.54
Anti-Cardiovascular Diseases
Currently, cardiovascular disease (CVD) is a great threat to human health. Previous studies have shown that the inflammation and risk of cardiovascular diseases have a strong consistent relationship, and this result has been proven by clinical trials and epidemiological studies.55 Studies have concluded that the activated pro-inflammatory cytokines, oxidative stress and inflammation and C-reactive protein (CRP) are key mechanisms in the development of CVD.56 Fu et al57 evaluated the role of neoglycyrrhetinic acid in sepsis-associated myocardial injury, and they discovered that GNA exerts anti-apoptotic, anti-fibrotic and anti-inflammatory effects in septic mice through inactivation of the MAPK/NF-κB pathway. Studies have shown that GA can inhibit cardiac hypertrophy and fibrosis induced by pressure or isoprenaline infusion by inhibiting the NF-κB pathways and proteasome, indicating that GA therapy may a new strategy for the treatment of cardiac hypertrophy and fibrosis.58
Rheumatoid Arthritis
Rheumatoid arthritis (RA) is a chronic, systemic disease characterized by inflammatory synovitis. It is characterized by polyarticular, symmetric, aggressive joint inflammation of the small joints of the hands and feet, often accompanied by extra-articular organ involvement and positive serum rheumatoid factor, which can lead to deformities of the joints. There is no specific treatment for rheumatoid arthritis. The aim of treatment is to maintain joint mobility and coordinated function, and different therapies are used at different stages of the disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to relieve pain and inflammation in the acute phase of RA. Early findings suggest that the ethyl acetate extract of gamboge appears to have a mechanism of action similar to NSAIDs rather than to steroids.59 Subsequent studies have demonstrated that GA is one of the NSAIDs that inhibit the development of RA by suppressing the levels of inflammatory molecules and cytokines.60 Wu et al61 revealed that the anti-inflammatory effect of GA in RA rats was mediated by modulation of the PI3K/Akt/mTOR signaling pathway.
Diabetes and Obesity
AMP-activated protein kinase (AMPK), an AMP-dependent protein kinase, is a key factor in the regulation of biological energy metabolism and also a key factor in the study of metabolism-related diseases, such as type 2 diabetes and obesity.62,63 Genetic and pharmacological studies have shown that AMPK is essential for the body to maintain glucose homeostasis. Zhao et al63 demonstrated for the first time that GA activates the AMPK signaling pathway by directly interacting with AMPK. Protein tyrosine phosphatase 1B (PTP1B) is involved in maintaining the balance of tyrosine protein phosphorylation and negatively regulates insulin signaling.34 The active compounds extracted from Garcinia hanburyi such as GA, moreollic acid, morellic acid, 10-methoxygambogenic acid, GNA, GA, morellinol, 10-methoxygambogin and desoxymorellin, were identified to be PTP1B inhibitors, they inhibit PTP1B in dose-dependent manner, the binding sites of GA and morellinol with PTP1B were studied, and it was revealed that the inhibitory activities are highly correlated with the caged motif and prenyl group in A ring.
Other Diseases
Recent research has shown that GNA ameliorates cardiac injury and dysfunction in LPS-induced septic mice by inhibiting cardiac apoptosis, fibrosis and inflammation through downregulation of p-JNK and p-NF-κB.57 In a recent work, binding affinities of xanthone compounds which including morellic acid, gambogellic acid, GNA, moreollic acid with SARS-CoV-2 main protease (Mpro) were predicted using the molecular docking technique, the results showed that morellic acid has a high-binding affinity towards SARS-CoV-2 Mpro, and this suggests that MA is a promising candidate for anti-COVID-19; however, this requires further detailed in vivo experimental estimation and clinical evaluation.64
Pharmacokinetic Studies and Countermeasures for Improving the Drug-Like Properties of Caged Polyprenylated Xanthones
To effectively utilize the curative effects of caged polyprenylated xanthones in clinic, an in vivo pharmacokinetic study of the drug is essential. In previous studies, GA was administered via intravenous injection; however, GA has an extremely short half-life in plasma.17,65 Administering GA intravenously to patients to treat tumors leads to side effects such as cardiotoxicity, liver damage and phlebitis.66 For these reasons, GA was not evaluated in Phase III clinical trials as an intravenous antitumor agent. In addition, the previous study found that, GA is poorly absorbed after gastrointestinal administration in rats and has low bioavailability in vivo; studies have shown that, after oral administration, GA is toxic to various rat organs.67,68 In view of the above-mentioned drawbacks, the clinical applications of GA administered via intravenous injection and orally are limited. Actually, many active ingredients of TCM with antitumor activity have strong hydrophobicity, and the conventional solubilization techniques cannot meet the needs of the development of insoluble drugs. To address these challenges, multiple studies have been conducted to refine the pharmacokinetic and pharmacodynamic performance of GA, chemical structure modifications, combination therapy and different types of nanoscale drug delivery systems (Table 2) and have been employed to modify or encapsulate GA while avoiding vascular irritation and organ toxicity in vivo. Rational medicinal modifications on GA will improve its physicochemical properties and drug-like characters. The chemical structural of GA is shown in Figure 1. Previous structure modifications of GA mainly focused on the 9,10-double carbon bond of a,b-unsaturated ketone, 6-hydroxyl group, isopentenyl groups and the 30-carboxyl group. It was found that the 9,10-double bond in a,b-unsaturated ketones is essential for the apoptosis-inducing activity, and the replacement of the acidic carboxyl group with ester and amide does not have much effect on the activity, it is also suggests that the hydrophilic face of GA may not have much relevance for its binding to biological targets. With the development of nano drug delivery systems, more and more elaborate and complex drug delivery systems are being designed, researchers have conducted studies on various nano-delivery systems of GA, including passive targeting, active targeting, tumor microenvironment response and bionic targeting, for example, the aqueous solubility of GA can be improved by chemical conjugation to a water-soluble polymer such as polyethylene glycol (PEG),69 Moreover, in order to control the release of GA, enhance its accumulation at tumor sites, and reduce side effects, multifunctional nanoparticles of GA with pH-sensitive and redox-responsive sensitivities as well as receptor-targeted responses were developed. However, more attention should be paid to the in vivo degradation and systemic toxicity of excipients used in these preparations, especially administered via intravenous injection. To date, no related oral or intravenous preparations of GA that have successfully passed clinical trials for market approval. In recent years, people have continued to explore new routes to deliver GA with improved bioavailability and reduced toxicity to serve as a breakthrough in tumor treatment. In addition to intravenous and oral administration, recent attention has been focused on improving the effectiveness of GNA through local delivery. Previously, researchers demonstrated that localized administration of GA with the help of chemical penetration enhancers could be a safe and effective therapy for the treatment of melanoma.70 In their follow-up study, compared with chemical penetration enhancers, ultrasound, and intravenous injection, GA exhibited the strongest antimelanoma activity with combined chemical penetration enhancers and ultrasound administration, as chemical penetration enhancers can increase the cavitation effect of US.71
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Table 2 GA Modifications |
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Figure 1 The chemical structure of GA. |
GNA is another major active ingredient extracted from the resin of gamboge, exhibits broader antitumor activity and less systemic toxicity than GA.72 To date, in vivo pharmacokinetic results in rats have shown that GNA is as poorly absorbed as GA after intragastric administration of Garcinia hanburyi extract. Additionally, the pharmacokinetic data of these two structurally similar xanthones are comparable, which means that slight changes in the position of the substituent on the alkyl side chain do not appreciably affect the in vivo pharmacokinetic properties of the compound.65,67,73–75 With the aim of overcoming the in vivo pharmacokinetic shortcomings of GNA for cancer therapy, recent studies have been trying to modify GNA with the aid of nanocarriers to improve its bioavailability and reduce its toxicity (Table 3). In 2013, our group prepared GNA-SLNs and compared the pharmacokinetic characteristics in rats after intraperitoneal injection of GNA solution and GNA-SLNs.76 Additionally, colloidal delivery systems were successfully fabricated for the targeted delivery of GNA. As demonstrated by the pharmacokinetic assay, after being encapsulated by the nano-delivery system, the residence time of GNA in the blood circulation was prolonged; in addition, the antitumor ability of the encapsulated GNA was significantly enhanced. In conclusion, the results of this study suggest that the nano-delivery system can potentially be used to deliver GNA. Notably, intravenous administration increases vascular damage and causes recurrent pain due to the vascular irritability of GA. As an attractive alternative, oral administration offers the following advantages, for instance, various dosage forms are available, relatively low production costs, ease of production and good patient compliance.77 Researchers have also designed oral dosage forms of GNA, such as, polydopamine nanoparticles were prepared for encapsulating and stabilizing GNA coated with sodium alginate after the modification of folic acid to achieve antitumor effect after oral administration and to improve the water solubility, bioavailability and tumor targeting of GNA.78 Our subject group also successfully isolated and extracted another component of Garcinia hanburyi, morellic acid (MA) (Compound 3, Table 1), which has also shown a good antitumor effect. As predicted, MA also has unfavorable pharmacokinetics; therefore, our group prepared MA NLCs to conquer this problem.79 However, the feasibility of producing this nano-delivery system, as well as the in vivo degradation and systemic toxicity of the excipients, need to be further investigated.
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Table 3 GNA Modifications |
In recent years, studies have shown that water processing could alter the bioavailability of five caged xanthones in Garcinia hanburyi, which could attenuate toxicity and increase their effects.80 Apart from the abovementioned studies, very few pharmacokinetic studies of other caged xanthones have been reported.
Interpretation of the Prediction Model
Physical and Chemical Properties
The pkCSM prediction results of physical and chemical properties (Table 4) show that the molecular weights of these caged polyprenylated xanthones are all greater than 500 with the exception of forbesione (Compound 46), the number of hydrogen bond acceptors is less than 10, the number of hydrogen bond donors is less than 5, and the logP values are between 5.0 and 8.5. The above parameters partially conform to the rule of Lipinski,174 and among these parameters, their drug-like properties are mainly limited by their larger molecular weight and higher lipid solubility.
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Table 4 Predicted Physical and Chemical Properties for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Absorption
The absorption parameter (Table 5) results show that these caged polyprenylated xanthones have poor water solubility, and lipid-soluble drugs are not absorbed as well as those that are water-soluble, especially after administration via the gastrointestinal tract.175 Additionally, these compounds have different degrees of Caco-2 cell permeability. In the pkCSM predictive model, high Caco-2 permeability would give predicted values greater than 0.90. Thus, GA and GNA are predicted to have high Caco-2 permeability. The intestinal absorption rates of these compounds ranged from 65% to 100%, well above the low intestinal absorption threshold of 30%, and they are considered to be well absorbed. These compounds also have certain skin permeability (they are not easily absorbed through the skin if the value is greater than −2.5).176 Notably, most of these compounds are substrates or inhibitors of p-glycoprotein (P-gp), suggesting that they may be excreted from cells by P-gp, which would lead to drug resistance.177 As P-gp inhibitors, these compounds may have significant pharmacokinetic implications for P-gp substrates, and may either be exploited for specific therapeutic advantages or result in contraindication.
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Table 5 Predicted Absorption Properties for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Distribution
In terms of distribution (Table 6), the steady-state volume of distribution (VDss) values of these xanthones are between −0.478 and 0.755, with those of GA and GNA being −0.154 and −0.478, respectively. The higher the VDss is, the more a drug is distributed in tissue rather than plasma.178 This means that the compound would be cleared quickly with a short retention time in vivo if the VDss value is less than −0.15. It can be seen from the unbound fraction179,180 that most of these compounds bind to serum proteins. The VDss values and unbound fraction jointly predict that these caged polyprenylated xanthones have a short residence time, are eliminated quickly, and do not accumulate easily in vivo. The predicted values of blood‒brain barrier (BBB) permeability (logBB) for these compounds are less than 0.3, which means that none of these compounds can easily cross the BBB. Notably, the logBB values for GNA and GA are less than −1, which means that they are poorly distributed to the brain. The predicted extent of BBB permeability and central nervous system (CNS) permeability suggest that these compounds do not easily penetrate the BBB or enter the CNS, and therefore, they do not produce side effects on the brain.
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Table 6 Predicted Distribution Properties for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Metabolism
In terms of metabolism (Table 7), cytochrome P450s (CYP450s) are an important class of enzymes involved in the metabolism of exogenous substances and mainly found in the liver. The two main isoforms responsible for drug metabolism are 2D6 and 3A4. Many drugs are deactivated by CYP450s; however, some are activated by these enzymes, which may lead to excessive drug accumulation if the compound is a CYP450 inhibitor.181 The prediction results indicated that these caged polyprenylated xanthones are substrates of CYP3A4 with the exception of forbesione (Compound 46), and some of them, including GNA, are also inhibitors of CYP3A4. This implies that when these xanthones are co-administered with drugs that are CYP3A4 substrates, they will interfere with metabolism and may induce drug accumulation in vivo, leading to toxicity.
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Table 7 Predicted Metabolism Properties for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Excretion
The excretion section (Table 8) describes the total clearance of the caged polyprenylated xanthones and whether they are organic cation transporter 2 (OCT2) substrates. Total clearance is related to bioavailability, which is important when determining dosing rates so that steady-state concentrations can be achieved. OCT2 is a renal uptake transporter that plays important roles in the disposition and renal clearance of drugs and endogenous compounds.182,183 From the predicted excretion data, these caged polyprenylated xanthones are not substrates of OCT2 and thus have a low risk of nephrotoxicity.
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Table 8 Predicted Excretion Properties for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Toxicity
In terms of toxicity (Table 9), these caged polyprenylated xanthones are not hERG inhibitors and therefore have no cardiotoxicity, were predicted to be negative in the AMES test and skin sensitivity test, and thus have no mutagenicity and do not irritate the skin; however, these compounds have certain Tetrahymena pyriformis and minnow toxicity. T. pyriformis is a protozoan bacterium with nutritional requirements, subcellular organelles and biochemical pathways similar to those of mammalian cells.184 This organism is commonly used to predict drug toxicity, and a predicted value greater than −0.5 is considered toxic. The value of minnow toxicity represents the concentration of a molecule that is necessary to cause the death of 50% of flathead minnows. This predicted value was below −0.3 for all of the caged polyprenylated xanthones, indicating that they may have aquatic toxicity.
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Table 9 Predicted Toxicity for the Caged Polyprenylated Xanthones in Garcinia hanburyi Provided by pkCSM |
Conclusion
In recent years, a lot of researches have been conducted on the pharmacological effects and formulation of caged polyprenylated xanthones in Garcinia hanburyi, with plenty of results achieved. However, the pharmacological study of the caged polyprenylated xanthones is still not deep enough, and there is no systematic research conducted on the quality standards and in vivo processes of active ingredients in Garcinia hanburyi. Based on the progress in research of the chemical constituents, pharmacological effects and modification methods of the caged polyprenylated xanthones, this paper presents a preliminary predictive analysis of their drug-like properties based on the ADME/T properties. These compounds have disadvantageous physical and chemical properties, including a large molecular weight, poor water solubility and low bioavailability in vivo, which is an obstacle to developing new drugs through the use of active ingredients contained in natural products. For the caged xanthones in Garcinia hanburyi, the author believes that subsequent studies could be carried out by considering the following points. (1) The new dosage forms and routes of administration. Currently, these compounds are mainly considered for injectable formulations. For example, based on the predicted results, these compounds have a certain degree of skin permeability, and it might be worth considering the possibility of dermal delivery. (2) The focus on researches for other indications. In addition to their use in cancer treatment, the caged xanthones can be studied and developed for other indications. Notably, gamboge has been used in traditional medicine as a potent purgative and to treat infected wounds. (3) The chemical modifications based on streamlined structure. Previous studies have shown that the 9,10-double bond in a,b-unsaturated ketones is essential for the antitumor activity and the acidic carboxyl group of GA without much effect on apoptosis-inducing activity. In terms of drug-likeness, the large molecular weights of these caged xanthones cause certain difficulties in both formulation studies and industrialization, and attempts can be made to simplify their structures while retaining the pharmacophores in the research and development of these ingredients. (4) The systematic studies on other caged xanthones. In addition to GA and GNA, we can also fully compare and explore the properties of other caged xanthones in Garcinia hanburyi, such as forbesione, which has been found to have a therapeutic effect on cholangiocarcinoma.185–187
Acknowledgments
This work was supported by the National Science and Technology Major Projects for “Major New Drugs Innovation and Development” (2009ZX09103-399) and the National Natural Science Foundation of China (82073923).
Disclosure
The authors report no conflicts of interest in this work.
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