Exploring the Potential of Ivy Leaf Extract Hederagenin in Functional Food Formulations

Green Spring Technology, as a leading provider of plant extract solutions, remains committed to identifying natural active ingredients with high application value. Today, we are focusing on a key pentacyclic triterpenoid compound derived from multiple medicinal plants—Hederagenin (Ivy Saponin), whose significant health-promoting potential is inspiring new ideas for formulators in the food, beverage, and dietary supplement industries.

Broad Sources, Natural Advantages:

Hederagenin is widely distributed in nature and is one of the active components of traditional medicinal plants such as Coptis, Honeysuckle, Clematis, Whitehead, and Fructus Schisandrae. This ensures a stable supply as a sustainable raw material, aligning with the strong market demand for natural and plant-based ingredients.

Breaking Through Bottlenecks: Technological Advances in Enhancing Bioavailability

Although natural Hederagenin poses solubility challenges, cutting-edge research has achieved significant breakthroughs.

Scientists have successfully developed a series of Hederagenin derivatives with significantly improved water solubility and enhanced bioavailability by innovatively modifying its molecular structure (primarily at the C-3, C-23, and C-28 positions) through chemical modifications such as esterification, amidation, succinylation, and the introduction of hydrophilic groups.These technical advancements open up new possibilities for exploring its applications in various end-product formulations.

1. Resource Distribution

Hederagenin is widely distributed in plants belonging to the families Caryophyllaceae, Caprifoliaceae, Ranunculaceae, Araliaceae, and Scrophulariaceae, with relatively abundant resources (Table 1).

2. Chemical Modification of Hederagenin Derivatives

Hederagenin is a pentacyclic triterpenoid compound whose structural components—the hydroxyl group at the C-3 position, the double bond at the C-12/C-13 position, the hydroxyl group at the C-23 position, and the carboxyl group at the C-28 position—can undergo chemical reactions to synthesise various derivatives.

2.1 Chemical Modification of the C-28 Carboxyl Group

Literature reports have used K₂CO₃ as a catalyst to react Hederagenin with different brominated alkanes (Figure 1), successfully modifying the C-28 carboxyl group and synthesising 23 alkyl esters with yields ranging from 35% to 90% [40].

Sun Lu et al. [41] synthesized C-28-methyl ester derivatives under anhydrous conditions using Hederagenin as the raw material through a reaction with potassium carbonate and methyl iodide.

Hong Kaiwen et al. [42] also reported the esterification of the C-28 carboxyl group with methyl iodide to obtain the corresponding methyl ester products.

In the literature [40], Hederagenin was used as the raw material, and under the conditions of O-benzotriazole-N,N,N', N'-tetramethylurea tetrafluoroborate (TBTU) as the coupling catalyst, it reacted with amine compounds, and by structurally modifying the carboxyl group at the C-28 position,six amide derivatives of Hederagenin were synthesised.

Wang Guohua et al. [43-44] used Hederagenin (0.4 mol) as the raw material, added N-hydroxy succinimide (NHS, 0.6 mmol) and tetrahydrofuran (THF, 10 mL), stirred, then added N,N'-dicyclohexylcarbodiimide (DCC, 1.2 mmol). NHS reacted with the C-28 carboxyl group to form a white powdery compound 1, which was unstable and needed to be used immediately.Compound 1 was then slowly added to 3-dimethylaminopropylamine (1.44 mmol), followed by triethylamine (3 mmol), to further modify the C-28 position, yielding compound 2, i.e., N-(3-dimethylaminopropyl)-ivy saponin-17-carboxamide,The synthesis route is shown in Figure 2.

Himo et al. [45] used ivy saponin as the raw material and reacted it with propyne bromide or propyne amine in TBTU/N,N-diisopropylamine/THF and K₂CO₃/DMF systems, respectively.The resulting products were subjected to a 1,3-dipolar cycloaddition reaction between the terminal acetylene and benzyl azide in the presence of copper sulfate pentahydrate and sodium ascorbate, yielding 31 C-28-modified 1,2,3-triazole derivatives. The synthesis route is shown in Figure 3.

Wu Yaomin et al. [46] dissolved Hederagenin (10 mmol) in 95% ethanol (80 mL), and sodium hydroxide (12 mmol) in 70% ethanol (80 mL). Under stirring at room temperature, the sodium hydroxide ethanol solution was added to the Hederagenin solution, reacted for 15 minutes, then heated at 50–60°C for 20 minutes.After vacuum evaporation of the solvent, the product was washed twice with water and recrystallised with 95% ethanol, yielding ivy saponin aglycone-28-carboxylic acid sodium salt.

헤데라제닌 C-3과 C-23포지션 파생형 2.2

Sun Lu [41] prepared ivy saponin-28-methyl ester (6.21 g) from the aforementioned hederagenin as raw material, dissolved 6.21 g in 100 mL of THF, added 25 mL of 100% acetic acid, and stirred at room temperature for 30 minutes. Slowly add 3 mL of acetic anhydride, and the acetic anhydride reacts with the C-3 and C-2 positions of the hederagenin ring, forming a ring-opening reaction. 25 mmol in 100 mL of THF, stirred at room temperature for 30 min, then slowly added 3 mL of acetic anhydride, which reacted with the hydroxyl groups at the C-3 and C-23 positions to yield 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,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. Ac₂O reacts with the hydroxyl group at the C-3 position, yielding the ivy saponin aglycone 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] reacted succinic anhydride (Succinicanhydride) 28 mmol with toluene (C₇H₈) 1000 mL and triethylamine (Et₃N) 300 mL, stirred and heated. When reflux occurred, 4.65 mmol of ivy saponin aglycone was added, and the mixture was refluxed for 8 hours.The succinic anhydride modifies the hydroxyl groups at the C-3 and C-23 positions, yielding hederagenin-3,23-disuccinate. Take 10 g of this derivative and dissolve it in 100 mL of anhydrous ethanol. Add a 3% sodium hydroxide solution at approximately 10 °C. Sodium hydroxide further modifies the C-3 and C-23 positions of the derivative, yielding the disodium salt of Hederagenin-3,23-disuccinate disodium salt, as shown in Figure 5.

2.3 Derivatives of Hederagenin at the C-12 and C-13 positions

Sun Lu [41] conducted structural modification studies on the C-12 andC-13 positions. 10.5 mmol of derivative 11 and 21 mmol of m-chloroperbenzoic acid (m-CPBA) were dissolved in 50 mL of trichloromethane(CHCl₃) 50 mL, placed the two 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 obtain the hederagenin derivative 12.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. cool the solution, adjust 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 시약, 그리고 가열 하에서 역류하여 그림 6에 나타낸 바와 같이 hederagenin sapogenin 유도체 15를 얻는다.

C-3, C-23, C-28포지션에서 헤데라제닌 파생형 2.4

Kim et al. [48] benzyl chloride (BzCl) was used to benzylify the hydroxyl group at position C-23 under dry pyridine conditions,and the carboxyl group at the C-28 position was structurally modified with tert-butyl diphenyl chlorosilane (TBDPSCl) in DMF, yielding the doubly protected hederagenin aglycone derivative 16 with a total yield of 80%.Under 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) conditions, treat the trisaccharide with phthalic anhydride, then treat at -78 °C with 2,6-d-tert-butyl-4-methylpyridine (DTBMP) and trifluoromethanesulfonic anhydride (Tf₂O) as activators, and adding the protected derivative 16, structural modification of the hydroxyl group at the C-3 position was performed, yielding derivative 17 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 THF, where the benzoic acid group was deprotected using potassium tert-butylate (KOt-Bu). Structural modifications at the C-3,C-23, and C-28 positions of derivative 17, yielding derivative 18 in 84% yield, as shown in Figure 7.

TONG et al. [49] found that derivative 19 was synthesized by acetylation with Ac₂O under dry pyridine conditions, followed by reaction with chlorobenzoyl chloride [(COCl)₂] in DCM, and then amination with 3-(1-piperazinyl) methyl 3-(1-piperazinyl) propanoate dihydrochloride, yielding derivative 20. Derivative 21 was obtained by hydrolysis of 20 in a methanol/THF/water solution, as shown in Figure 8.

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-olean-12-en-28-oic acid]; This was then reacted with (COCl₂)₂ in dichloromethane under ice bath conditions for 1 hour, followed by addition of dichloromethane and vacuum recovery. After dissolving the dichloromethane, the pH was adjusted to 9–10 with Et₃N,add ethanolamine (NH₂CH₂CH₂OH) for reaction, where ethanolamine modifies the C-28 position, yielding the hederagenin derivative {2-[(3β,4a)-3,23-diacetyl-quercetin-12-en-28-yl]-aminoethanol}, see Figure 8.

3 Scientific Research

In recent years, several scientific studies have explored the role of Hederagenin and its derivatives in specific biological models:

3.1 Neurological Studies

Some studies have used cell models (e.g., corticosterone-induced PC12 cells) and animal behaviour models (e.g., behavioural despair model, chronic unpredictable mild stress model) to observe the specific biological effects of Hederagenin and its extracts (e.g., ivy leaf extract FAE) in these models, such as influencing the levels of certain stress-related hormones (e.g., ACTH, CORT) or cellular vitality indicators.These foundational studies provide scientific clues for further exploring its potential applications in related fields.

3.2 Microbial and Inflammation-Related Research

 In vitro experiments have reported the effects of Hederagenin on the growth of certain specific microorganisms (e.g., Enterococcus faecalis, Staphylococcus aureus) (e.g., minimum inhibitory concentration MIC = 31 mg/L) and its activity against specific parasitic models (e.g., Leishmania parasites).Animal experiments also suggest its potential effects in certain pain models. These findings indicate its biological characteristics warranting further investigation.

The aforementioned research results are primarily based on laboratory models (cells, animals). The specific application efficacy of Hederagenin as a raw material component in final food, beverage, or dietary supplement products must be determined by customers in accordance with regulatory requirements of the target market through rigorous product development, safety assessment, and compliance claims.

4. Application Prospects

Based on its unique chemical structure, improved physical properties (such as solubility), and current scientific research focus, Hederagenin and its derivatives are considered to have potential application value in the development of innovative functional food, beverage, and dietary supplement formulations targeting specific health claims. Formulation designers can explore its application potential in relevant product concepts by combining existing scientific research insights and target market compliance requirements.

Green Spring Technology provides high-quality Ivy Leaf Extract Hederagenin compliant with international standards and scientifically validated natural raw materials.

We offer customised solutions to meet specific formulation requirements (e.g., solubility, stability optimisation).

Contact us immediately to obtain detailed Hederagenin COA, compliance documents, and R&D support information, and explore how to safely and compliantly integrate this innovative ingredient into your product formulations!

참조

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[5] 리주펑, 천진푸, 탕샤오리 등이 있다.HPLC에 의한 Cynanchum atratum의 공급원에 따른 아이비 사포닌의 함량 확인 [J.New Chinese Drugs and Clinical Pharmacology, 2013, 24(6):606-609.

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[10] 관영리, 류자무, 서영난.연구논문:Pulsatilla 식물의 Triterpenoid Saponins 및 생물학적 활성에 관한 연구 (J.선양제약대학교 논문집 2009, 26 (1):80-83.

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