What Is Ivy Leaf Extract Hederagenin?

Ivy leaf extract Hederagenin, also known as (3β, 4α)-3, 23-dihydroxy-12-en-28-oic acid, with the molecular formula C30H48O4, belongs to the pentacyclic triterpenoid compounds. It is widely distributed in various medicinal plants such as Cynanchum, Clematis, Pulsatilla, Lonicera, and Schisandra chinensis. Due to the poor solubility, low bioavailability, and poor oral administration efficacy of ivy saponins, research on the pharmacological activity of Hederagenin is relatively limited at present, and its clinical application is correspondingly restricted.

To address this, domestic and international researchers have structurally modified Hederagenin, synthesizing a number of derivatives with improved water solubility and bioavailability. The structural modifications primarily occur at positions C-28, C-3, and C-23. Current studies on drug activity indicate that ivy leaf extract and ivy saponins exhibit pharmacological effects and biological activities such as antitumor, antidepressant, antibacterial, anti-inflammatory, and antidiabetic properties. This study systematically reviews and analyzes the resource distribution, structural modification, and pharmacological effects of Hederagenin, laying the foundation for further improving its bioavailability and pharmacological activity, and providing scientific basis for the preparation of new Hederagenin-related derivatives and their pharmacological activity studies.

1 Resource Distribution

Hederagenin is widely distributed in various plants belonging to the families of Apiaceae, Caprifoliaceae, Ranunculaceae, Araliaceae, and Scrophulariaceae, with relatively abundant resources. See Table 1.

2 Hederagenin Derivatives

Hederagenin, extracted from ivy leaves, belongs to the pentacyclic triterpenoid compounds. The hydroxyl group at the C-3 position, the double bonds at the C-12 and C-13 positions, the hydroxyl group at the C-23 position, and the carboxyl group at the C-28 position can undergo corresponding transformation reactions, enabling the preparation of numerous new Hederagenin derivatives.

2.1 Hederagenin C-28 Derivatives

In the literature, K₂CO₃ was used as a catalyst, and Hederagenin was reacted with different bromoalkanes [40], as shown in Figure 1. After structural modification of the carboxyl group at the C-28 position, 23 alkyl esters were synthesized, with yields ranging from 35% to 90%. Sun Lu [41] used 15 mmol of Hederagenin as the raw material, under conditions of 37.50 mol of anhydrous potassium carbonate and 50 mL of dried N,N-dimethylformamide (DMF), reacted with 30 mmol of iodomethane, to modify the carboxyl group at the C-28 position, synthesizing hederagenin-28-methyl ester. Hong Kaiwen et al. [42] synthesized hederagenin-28-methyl ester by reacting hederagenin with iodomethane to modify the carboxyl group at the C-28 position. 

In the literature [40], hederagenin was used as the raw material, and under the conditions of O-benzotriazine-N,N,N',N'-tetramethylurea tetrafluoroborate tetrabutyl (TBTU) as the coupling catalyst, it reacted with amine compounds, structurally modifying the carboxyl group at the C-28 position, six amide derivatives of Hederagenin were synthesized. Wang Guohua et al. [43-44] used 0.4 mol of Hederagenin as the raw material, added 0.6 mmol of N-hydroxy succinimide (NHS), 10 mL of tetrahydrofuran (THF), stirred, then added 1.2 mmol of N, N'-dicyclohexylcarbodiimide (DCC) 1.2 mmol, allowing NHS to react with the carboxyl group at the C-28 position, yielding a white powdery compound 1. Compound 1 is unstable and prone to degradation; immediately add compound 1 slowly to 1.44 mmol of 3-dimethylaminopropylamine, followed by slowly adding 3 mmol of triethylamine. The 3-dimethylaminopropylamine further modifies the C-28 position, synthesizing compound 2, i.e., N-(3-dimethylaminopropyl)-ivy saponin-17-carboxamide, as shown in Figure 2.

Himo et al. [45] used ivy saponin as the starting material and reacted it with propargyl bromide or propargylamine under various conditions, including TBTU, N,N-diisopropylamine, THF, and K₂CO₃, DMF. The products were then reacted with terminal alkynes and benzylamine azides via a 1,3-dipolar cycloaddition reaction in the presence of copper sulfate pentahydrate and sodium ascorbate, using the 1,3-dipolar cycloaddition reaction between terminal acetylene and benzyl azide to prepare 31 C-28-modified 1,2,3-triazole derivatives, as shown in Figure 3.

Wu Yaomin et al. [46] dissolved 10 mmol of hederagenin in 80 mL of 95% ethanol, dissolved 12 mmol of sodium hydroxide in 80 mL of 70% ethanol, and stirred at room temperature. The sodium hydroxide ethanol solution was added to the hederagenin ethanol solution, and after 15 minutes, the resulting mixture was heated at 50–60°C for 20 minutes, the solvent was removed under reduced pressure, the product was washed twice with water, and recrystallized with 95% ethanol to obtain ivy saponin aglycone-28-carboxylate sodium salt.

2.2 Hederagenin C-3 and C-23 position derivatives

Sun Lu [41] used the hederagenin-derived ivy saponin-28-methyl ester (6.21 g) as raw material and dissolved it in 100 mL of THF with 1.25 mmol of 4-dimethylaminopyridine (DMAP). stirred at room temperature for 30 min, and slowly added 3 mL of acetic anhydride. The acetic anhydride reacted with the hydroxyl groups at the C-3 and C-23 positions, yielding the hederagenin derivative 7. Similarly, dissolve 0.21 mmol of derivative 3 in anhydrous DCM, stir under ice bath conditions for 10 minutes, add 1 mL of benzylbromide (BnBr) and 69 mg of 60% NaH, and react. BnBr reacts with the hydroxyl group at the C-23 position, yielding hederagenin derivative 9.

React 0.10 mmol of derivative 7 with 2 mL of Py, 1 mL of Ac₂O, and 10 mg of dimethylaminopyridine. The hydroxyl group at the C-3 position reacts with Ac₂O to yield the ivy saponin derivative 8. React 0.09 mmol of derivative 9 with 2 mL of Py, 1 mL of Ac₂O, and 12 mg of DMAP. The hydroxyl group at the C-3 position reacts with Ac₂O to yield hederagenin derivative 10, as shown in Figure 4.

Ma Renqiang et al. [47] dissolved succinic anhydride (Succinicanhydride) 28 mmol in toluene (C7H8) 1000 mL and triethylamine (Et3N) 300 mL, stirred and heated, added 4.65 mmol of hederagenin 4 when reflux occurred, and refluxed for 8 h. The succinic anhydride modified the hydroxyl groups at the C-3 and C-23 positions, yielding hederagenin-3,23-disuccinate. Next, 10 g of this derivative was dissolved in 100 mL of anhydrous ethanol, and a 3% sodium hydroxide solution was added at approximately 10°C. The sodium hydroxide solution further modifies the C-3 and C-23 positions of the derivative, yielding the disodium salt of Hederagenin-3,23-dihydrogen succinate, as shown in Figure 5. 

2.3 Hederagenin C-12 and C-13 position derivatives

Sun Lu [41] conducted structural modification studies on the C-12 and C-13 positions, dissolving 10.5 mmol of derivative 11 and 21 mmol of 3-chloroperbenzoic acid (m-CPBA) in 50 mL of chloroform (CHCl3), respectively. The two solutions were placed in a round-bottom flask, protected from light, and stored for 2 days. m-CPBA) 21 mmol were dissolved in 50 mL of trichloromethane (CHCl₃), placed in a round-bottom flask, and stored in the dark for 2 days. The mixture was then washed with 5% FeSO₄ solution, Na₂CO₃ solution, HCl solution, and water, dried, and distilled under reduced pressure to the hederagenin derivative 12 was obtained. Dissolve 7 mmol of derivative 12 in 50 mL of hot ethanol, add 35 mmol of hydroxylamine hydrochloride (NH₂OH·HCl) and 56 mmol of anhydrous CH₃COONa, and reflux for 3 hours. After cooling, adjust the solution to acidity with dilute hydrochloric acid and filter to obtain the ivy saponin aglycone derivative 13. Dissolve 5 mmol of derivative 13 in 50 mL of dry pyridine, slowly add POCl₃ solution under ice bath conditions, cool the solution, adjust to acidity with dilute hydrochloric acid, and filter to obtain hederagenin derivative 14. Dissolve 2 mmol of derivative 14 in 50 mL of dry benzene (C₆H₆), add 2 mmol of Lavesson's reagent, and reflux under heating to obtain the hederagenin sapogenin derivative 15, as shown in Figure 6.

2.4 Hederagenin derivatives at positions C-3, C-23, and C-28

Kim et al. [48] under dry pyridine conditions, benzyl chloride (BzCl) was used to benzylify the hydroxyl group at the C-23 position, and tert-butyl diphenyl chlorosilane (TBDPSCl) was used to modify the carboxyl group at the C-28 position under DMF conditions, obtaining the doubly protected ivy saponin aglycone derivative 16 with a total yield of 80%. Under 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) conditions, the trisaccharide was treated with phthalic anhydride, followed by treatment at –78 °C with 2,6-dibutyl-4-methylpyridine (DTBMP) and trifluoromethanesulfonic anhydride (Tf₂O) as activators, and adding the protected derivative 16. By structurally modifying the hydroxyl group at the C-3 position, derivative 17 was obtained with a yield of 70%. The tert-butyl diphenylsilyl (TBDPS) protecting group of derivative 17 was removed using tetrabutylammonium fluoride (TBAF), followed by a one-pot reaction in which the benzoic acid group was deprotected with potassium tert-butylate (KOt-Bu) in THF. Structural modifications were then performed on the C-3, C-23, C-28 positions of derivative 17, yielding derivative 18 in 84% yield, as shown in Figure 7.

TONG et al. [49] reported that derivative 19 was synthesized by acetylation with Ac₂O under dry pyridine conditions, followed by reaction with DCM and [COCl₂] (chlorobenzene), and then amination with methyl 3-(1-piperazinyl) propanate dihydrochloride, yielding derivative 20. Derivative 21 is obtained by hydrolyzing 20 in a methanol/THF/water solution. 

He Yufang et al. [50] reacted hederagenin with Ac₂O in dry pyridine at 80°C under stirring conditions. Ac₂O modified the C-3 position of the ivy saponin aglycone, C-23 positions of the ivy saponin aglycone, yielding the ivy saponin aglycone derivative [(3β, 4a)-3,23-diacetyl-quercetin-12-ene-28-acid]; This was then reacted with (COCl₂)₂ in dichloromethane under ice bath conditions for 1 h, followed by addition of dichloromethane and vacuum recovery. After dissolving the dichloromethane, the pH was adjusted to 9–10 with Et₃N, and ethanolamine (NH₂CH₂CH₂OH) was added for reaction. The ethanolamine modifies the C-28 position, yielding the hederagenin derivative {2-[(3β,4a)-3,23-diacetyl-olean-12-en-28-yl]aminoethanol}, as shown in Figure 8.

3 Pharmacological effects

Hederagenin is widely distributed in various medicinal plants, but its content is relatively low. Studies have shown that hederagenin possesses multiple pharmacological effects, including antitumor, antidepressant, antibacterial, anti-inflammatory, and antidiabetic activities.

3.1 Antitumor Activity

Xu Fuchun [51] found that the extract of ivy leaves, ivy saponin, exhibited strong cytotoxicity against human liver cancer HepG2 cells, human gastric adenocarcinoma SGC-7901 cells, and human promyelocytic leukemia HL-60 cells; against HL-60 cells, exhibiting low-concentration inhibition and high-concentration lethality, with a certain concentration- and time-dependent relationship. Further studies using Hoechst 33258 fluorescence staining and DNA ladder electrophoresis indicated that hederagenin can induce apoptosis and death in HL-60 cells.

Liu Baoxinzi et al. [52-53] found that hederagenin significantly inhibited the proliferation, adhesion, invasion, and migration of human colon cancer cells (LoVo) and gastric cancer cells (MGC-803) as the concentration of ivy saponin increased and the duration of exposure to the cells increased. Yin Shuyuan et al. [54] found that as drug concentrations increased, the inhibitory effects of Hederagenin, fluorouracil, oxaliplatin, and their combination on HT-29 cell growth also increased, with enhanced synergistic effects at high concentrations; low concentrations of Hederagenin combined with fluorouracil and oxaliplatin exhibited a good synergistic effect on HT-29 cells; the clonogenic inhibition rate of the combined treatment group was significantly higher than that of the single-drug group.

Chen Yan et al. [55-56] found that taxus saponin significantly inhibited TGB-β1-induced proliferation of SW480 cells, as well as the epithelial-mesenchymal transition and invasive migration capabilities of SW480 cells. Li Xinxun et al. [57] found that ivy saponin significantly inhibited the growth of MCF-7 breast cancer tumors in nude mice and A549 lung cancer tumors in nude mice, exhibiting a certain degree of concentration dependence. Zhao Zhenxia et al. [58] found that hederagenin significantly inhibited the proliferation, migration, and invasion of prostate cancer cells, exhibiting a certain degree of time and dose dependency.

Yang Xiaolin [59] found that hederagenin significantly inhibited the growth of breast cancer cells (MCF-7), lung cancer cells (A549), liver cancer cells (Hep3B), stomach cancer cells (MGC-803), colon cancer cells (LoVo), ovarian cancer cells (HO-8910PM), endometrial cancer cells (HEC-1), leukemia cells K562, and esophageal squamous cell carcinoma cells Eca-109. Jiang Yiheng [60] found that Hederagenin exhibits significant inhibitory effects on human liver cancer cells SMMC-7721, Bel-7402, human ovarian cancer cells HO8910, human prostate cancer cells PC-3M, human lung adenocarcinoma cells A549, human colon cancer cells HCT-8, human esophageal cancer cells CaEs-17, human brain glioma cells U251, human gastric cancer cells BGC-823, and human gastric adenocarcinoma cells SGC-7901, with IC50 values all <0.01 g·L^(−1).

3.2 Antidepressant effects

Zhou Dan [61] found that the main component of ivy leaf extract (FAE) is hederagenin. After administering FAE (25, 50, 100 mg·kg^(−1)) to mice with behavioral despair and chronic unpredictable mild stress (CUMS)-induced depression, the results showed that FAE significantly improved both types of depressive behavior. ZHOU et al. [62] found in experiments measuring HPA axis-related hormones that FAE significantly reduced plasma adrenocorticotropic hormone (ACTH) and serum cortisol (CORT) levels in CUMS-stimulated rats, indicating that FAE restores HPA axis function in depressed rats to normal levels. Liang Baofang et al. [63] found in a corticosterone-induced PC12 cell damage model that after administration of Hederagenin at concentrations of 4.23 μmol/L and 8.46 μmol/L, the cell survival rates increased by 24.60% and 32.74%, respectively; this indicates that hederagenin has a significant inhibitory effect on corticosterone-induced cellular damage.

3.3 Antimicrobial and Anti-inflammatory Effects

Ndjateu et al. [64] found that hederagenin isolated from Barteria fistulosa exhibited strong inhibitory effects against Enterococcus faecalis and Staphylococcus aureus, with minimum inhibitory concentrations (MIC) of 31 mg·L^(−1). Choi et al. [65] confirmed the analgesic and anti-inflammatory effects of hederagenin isolated from the stems of Akebia quinata through mouse hot plate and tail-flicking experiments, confirmed that Hederagenin isolated from the stem of Akebia quinata, a plant belonging to the Lardizabalaceae family, exhibits analgesic and anti-inflammatory effects. Majester-Savornin et al. [66] found that Hederagenin isolated from the leaves of Western Ivy (Aralia elata) exhibits bactericidal activity against Leishmania larvae and tropical Leishmania parasites, and that Aralia saponins exhibit significant activity against the acontitive stage.

3.4 Antidiabetic effects

Zhang Xiantao [67] found that diosgenin with a hederagenin content of over 70% exhibited significant inhibitory activity against α-glucosidase. Zhao Quancheng et al. [68] found that hederagenin can reduce blood glucose and glucagon levels in normal mice, promote insulin secretion, and increase liver glycogen and muscle glycogen levels.

3.5 Other effects

Wu et al. [69] confirmed that hederagenin improves motor dysfunction in a PD mouse model and exhibits neuroprotective effects. Additionally, hederagenin is regarded as a new autophagy enhancer. Choi et al. [70] found that Hederagenin exhibits significant inhibitory effects on pain in rheumatoid arthritis. Zhao Quancheng et al. [71] found that Hederagenin has preventive effects on hyperlipidemia in experimental rats and mice, and significantly improves the hemorheological characteristics of blood in experimental rats with hyperlipidemia.

4 Discussion

Hederagenin is abundant in nature and widely distributed in various plants such as the Apiaceae, Caprifoliaceae, Ranunculaceae, Araliaceae, and Patriniaceae families, offering good development potential. The pharmacological effects of ivy saponins are currently primarily focused on antitumor, antidepressant, antibacterial, and anti-inflammatory activities; however, systematic studies on their mechanisms of action are lacking. Hederagenin also has issues such as poor solubility, low bioavailability, and poor oral efficacy [43]. Therefore, structural modification of hederagenin is particularly important. Currently, structural modifications at the C-3, C-23, and C-28 positions of hederagenin are relatively common, while modifications at the C-12, C-13 positions are relatively rare. Related studies have shown that after carboxymethylation or acylation at the C-28 position, the lipophilicity of Hederagenin can be significantly improved, facilitating further structural modifications of the hydroxyl and sugar groups [72]. Further research should be conducted on the structural modifications of hederagenin to enhance its bioavailability and multifaceted pharmacological activities, and to elucidate its underlying mechanisms. With the continued development of hederagenin derivatives and advancements in pharmaceutical technology, hederagenin is expected to unlock its significant potential for clinical applications.

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