高麗人参エキスギンセノシドの異なる種類の研究

Ginsenosides (GS)高麗人参、高麗人参、アメリカ人参などの貴重な薬草の主な有効成分です。これらはトリテルペノイド配糖体に属し、配糖体(ギンセノシド)と糖基から構成される[1]。ギンセノシドは、抗腫瘍作用[2]、抗炎症作用[3]、抗疲労作用[4-5]、抗酸化作用[6]など幅広い生物活性を有しており、二次性のギンセノシドはさらに優れた活性を示す。しかし、高活性二次ギンセノシドは、低含有量、低水溶性、低生物学的利用能、短い半減期などの問題を有し[7]、食品医療や生物医学の分野でのギンセノシドの適用が制限されている。

Structural modification is an important means to improve の生物活動のginsenosides, improve pharmacokinetic properties とreduce toxicity。 Ginsenosides are usually composed ののhydrophobic aglycone linked to 1–4 hydrophilic sugar moieties, so they can be modified でthese two ways。 At present, のmodificatiにのginsenosides mainly adopts chemical modificatiにstrategies, とginsenoside 派生商品with better activity とphysicochemical properties are obtained によってmodifying the aglycone structure or modifying the sugar chaで[8]。 In terms のstructure, the cycloalkane structure のaglycone is stable, とit is difficult to directly modify the aglycone backbone.

The current main modificatiにstrategies focus on the hydroxyl group on the aglycone, と派生商品with diverse structures are obtained through synthetic methods such としてesterification, oxidation, the introduction のheterocycles, or molecular hybridization. Modifications to the sugar chain mainly involve the extension のthe sugar moiety or modification のhydroxyl group on the sugar chain. Studies have shown that the type, number and binding site のthe sugar group on the ginsenoside parent nucleus are closely related to the biological activity of ginsenosides [18-20]. In general, the relationship between the number of sugar groups and the anti-tumoractivity of ginsenosides is as follows: aglycone > monosaccharide glycoside > disaccharide glycoside > trisaccharide glycoside > tetrasaccharide glycoside. Therefore, modifying the sugar chains of ginsenosides is of great significance for improving をbiological activity. This paper reviews recent progress in the chemical modification and biological activity of ginsenosides, elucidates the structure-activity relationship, and summarizes the characteristics and laws of structural modification of ginsenosides, providing a reference for subsequent structural modification.

1ギンセノシドの分類と構造的特徴

アグリコンの構造の違いにより、ダムマラン型、オレアナン型、オコチロール型の3つのタイプに分けることができます。Dammarane-typeginsenosides can be further subdivided into protopanaxdiol (PPD) and propanaxatriol (PPT) according to the position of the substituent group attached to the aglycone.

1.1 Dammaraneタイプ

Dammarane-type ginsenosides include PPD and protopanaxatriol (PPT), which are tricyclic triterpene saponins. Common protopanaxadiol ginsenosides include C-K (1), Rh2(2), Rd (3), Rg3 (4), Rb1 (5), Ra1, Ra2, Ra3, Rb2 and panaxadiol (PD) (Fig. 1). Since ginsenosides 1, 2, 4 and 5 have stronger biological activity, their 合成and modification have attracted much attention [9-11]. Common protopanaxatriol-type ginsenosides mainly include Rh1 (6), Rg1 (7), Rg2 (8), Re, Rf, F1, F3, F5 and glycosylated panaxatriol (PT) (see Figure 2), among which 6, 7 and 8 have been studied extensively [8, 12].

1.2オレアノール酸型

Oleanolic acid type ginsenosides are pentacyclic triterpene saponins, which are formed by the glycosylation of oleanane type saponins (OATS) at the C-3 and C-28 positions. Common oleanolic acid-type ginsenosides include R3 (9), Ro (10), and R4 (11), among others [13-14] (see Figure 3).

1.3 Ocotillolタイプ

Ocotillol typesapogenins (OTS) can form four conformations: (20S24S), (20R,24R), (20S, 24R) and (20R,24S), depending on the configuration of the C-20 and C-24 linked sugar moieties. Commonly-found ginsenosides of the Oxytropae type include F11 (12), RT5 (13), RT2 (14), etc. [15-17] (see Figure 4).

2ギンセノシドの構造変化と構造活性相関

2.1エステル化修正

Ginsenosides水への溶解度が低く、脂肪への溶解度が低いため、生物学的利用能が低下し、健康維持および治療効果が低下します。薬物分子の理想的な親油性は、その生物学的利用能と臨床的有効性を確保するために一定の範囲内である必要がある[8]。薬物動態学的研究によると、ギンセノシドは経口投与後に腸内細菌叢によって加水分解され、加水分解によって生成された代謝物は静脈を介して肝臓に吸収され、そこで脂肪酸と反応して脂肪酸エステル化合物を形成することが示されている[21]。さらなる研究では、脂肪酸と結合したギンセノシド誘導体は、細胞内での細胞毒性が低く、居住時間が長く、より持続的な効果があることが示されている。一方、細胞膜は主に脂質で構成されているため、脂溶性エステル誘導体は膜全体の透過性を向上させ、望ましくない薬剤の経口吸収を促進することができます。この新知見は、ギンセノシドの修飾についての考えをもたらしている。有機酸(脂肪酸、芳香酸、無水)、アミノ酸、無機酸(硫酸)などの酸を用いたギンセノシドの修飾は、ギンセノシド誘導体の研究のための重要な戦略である。

2.1.1有機酸の修飾

Liang etアルreacted the hydroxyl group at the C-3 position of ginsenoside Rh2 (20S-Rh2, 2) with two 6-maleimidocaproic acid and 11-maleimidoundecanoic acid derivatives with hydrophilic functional groups and different carbon chain lengths to obtain the esterified derivatives 15 and 16 (see Figure 5). Compared with Rh2, the solubility of the two modified products increased by about 4 times and 2 times, respectively. In vitro anti-proliferation activity tests showed that compound 15, which has a shorter carbon chain, exhibited higher 抑制activity against the HeLa cell line, while compound 16, which has a longer carbon chain, did not show anti-proliferative activity [22]. Li etアルreacted decanoic acid, cyclohexanecarboxylic acid and isobutyric acid reacted with the C-20 hydroxyl group of ginsenoside C-K to synthesize three ginsenoside C-K monoesterified derivatives (17–19) [23] (see Figure 5).

の増加抑制政策において乳がんを発症さMCF-7セルでの抑制活動化合物18、19 25μmol / Lを大きく上回ってginsenoside C-K、複合17抑止効果を見せなかった、ことを示すginsenoside派生商品short-chain脂肪酸anti-tumor活動の強化で修飾long-chain脂肪酸で修飾に比べ他の研究[24 - 27]でも修正されているshort-chain fatty acid saponin derivatives not only have optimized physicochemical properties, but also have better anti-tumor 効果than long-chain fatty acid esters.

Li etアル合成a fully acetylated derivative of ginsenoside C-K by polyesterification modification, except for the glucose-based C-6 hydroxyl group [28] (see Figure 5). Anti-tumor activity tests showed that compared with C-Kit can inhibit the proliferation of multiple tumor cell lines at lower concentrations, while significantly inhibiting tumor growth in a hepatocellular carcinoma xenograft model without side 効果on major organs.

It can be seen that after esterification modification of ginsenoside C-Kits cytotoxicity is reduced and its antitumor activity is increased. Wang etアルreacted the C-3 hydroxyl group of PD with benzoic acid derivatives, amino acids and tetrachlorophthalic anhydride to obtain a series of PD derivatives 21–31 [29] (see Figure 5). Anti-tumor proliferation tests showed that most of the compounds had inhibitory effects on cancer cell lines, including human liver cancer cells HepG-2, human lung cancer cells A549, human breast cancer cells MCF-7, and human colon cancer cells HCT-116. Compared with PDginsenoside derivatives 22, 23, and 26 showed significant inhibitory effects on cancer cell proliferation. for example, 22 had the lowest IC50 value for A549 (IC50 = 18.91 ± 1.03 μmol/L), while for MCF-7 cells, compound 23 showed better inhibitory activity (IC50 = 8.62 ± 0.23 μmol/L). This result shows that the introduction of an aromatic acid into ginsenosides can also significantly improve antitumor activity.

The above-mentioned structure-activity relationship shows that the introduction of short-chain fatty acids into ginsenosides exhibits better activity than long-chain fatty acids. The number of esterification modification sites (monoesters and polyesters) and the type of acid (fatty acids and aromatic acids) have no significant 効果on biological activity.

2.1.2アミノ酸の修飾

25-Hydroxyl-protopanaxdiol (25-OH-PPD) (34), a 自然compound isolated からginseng fruit,顕著な抗腫瘍活性と低副作用と高い絶対経口バイオアベイラビリティの利点を有します。yuanら[30]は、独自の生理機能と薬効を発揮する非タンパク質アミノ酸と組み合わせ、一連の新しい25- oh-ppd誘導体を設計・合成した(図6参照)。例えば9段の複合33反対antitumor活動示し、HCT116 BGC-823セル線4.76μの値がIC50 mol / Lと6.38%μmol / L,(表1参照)。この他、アミノ酸派生物25-OH-PPD(46-59)も展示antitumor活動[31](表1参照)。

As can be seen from Table 1, the IC50 values of some non-protein amino acid modified products are greater than 100 μmol/Lwhile the anti-tumor activity of protein amino acid modified products is generally better than that of non-protein amino acid modified products, and their IC50 values are all lower than 30 μmol/L. On the other hand, the amino acids on ginsenoside derivatives with an IC50 value of less than 10 μmol/L for anti-tumor proliferation all have Boc protective groups, and removing the Boc protective groups significantly reduces the anti-tumor activity of the product, which indirectly indicates that increasing the lipid solubility of the product through esterification can significantly increase the biological activity of ginsenoside derivatives.

2.1.3無機酸の修飾

現在の無機酸の改質は主にスルホン化試薬のクロロスルホン酸を使って上の水酸基と反応するginsenoside sugar chain to form a sulfonate, which is then converted to a salt by neutralization with pyridine. As the introduction of a sulfate group increases the polarity of the ginsenoside derivative, solubility is improved. It has been reported that the anticancer activity of sea cucumber saponins, which have a similar structure to ginsenosides, is related to the sulfate group,the fewer sulfate groups present on the sugar chain, the stronger the 抗がんactivity [32].

Based on these findings, Guo etアル[33] used the chlorosulfonic acid-pyridine method to sulfate modify ginsenosides. The resulting derivative SMTG-d3 enhanced natural killer cell activity by promoting the proliferation of T lymphocytes and the production of IFN-γ and TNF-α cytokines. Compared with ginsenoside, SMTG-d3 not only reduces cytotoxicity, but also further enhances antitumor immune activity. Previously, Fu etアル[34-36] also used this method to convert the C-6 hydroxyl group 20 (S) -ginsenosideRh2to a sulfonate ester and synthesized two new derivatives 60 and 61 with greatly improved solubility (see Figure 7). Further studies have found that both derivatives can enhance 消炎and immune effects by blocking mitogen-activated protein kinase and the 釈放of pro-inflammatory mediators 誘導by activation. This shows that the sulfation of ginsenoside derivatives can increase their solubility, thereby enhancing 活動such as 消炎and anti-tumor effects.

酸化2.2修正

The planar double bond on the ginsenoside side chain and the hydroxyl group in the aglycone structure provide reaction sites for oxidation modification, making it possible to oxidize the C-17 side chain and のand C rings of some ginsenosides. Studies have shown that the double bond on the ginsenoside side chain is one of the reasons for its low solubility [37]. Ginsenosides can increase their solubility in water by reducing the degree of unsaturation or adding ionizable groups such as carboxyl groups through oxidative modification, thereby enhancing their biological activity.

Wong etアル[38] oxidized the double bond on the side chain of ginsenoside 20(R)-Rh2 (2) to obtained a derivative 20(R)-Rh2E2 (62) that can effectively prevent the development of colorectal cancer induced by oxidized azomethane/dextran sulfate sodium salt (AOM/DSS) (see Figure 8). This epoxide compound also has inhibitory activity against other cancer cell lines. For example, its IC50 for lung cancer cells (LLC-1) is 56 μmol/L.

It has been found that PPD is metabolized in the human liver to form C-20-24 epoxide, which contains the Pyxinol skeleton and has good anti-inflammatory activity [39]. Wang etアルepoxidized 20(S)-PPD and then subjected to Dess-Martin oxidation, selective reduction with NaBH4, condensation and deprotection reactions to obtain a series of amino acid-modified C-12 oxidized Pyxinol derivatives [40] (see Figure 9). In vitro cytotoxicity tests showed that most derivatives did not exhibit significant toxic effects.

Using the Griess method to test the inhibitory activity of these derivatives on nitric oxide in RAW264.7 macrophages, derivatives 63a, 63b, 63c, 63d, 64e, 66b, and 66c showed good anti-inflammatory activity (inhibition rates of 48% to 85%), even better than Y13 (known as the Pyxinol derivative with the best anti-inflammatory activity at the C-12 site, with a hydroxyl group, and an inhibition rate of <40%) and the clinically approved glucocorticoid steroid drug hydrocortisone sodium succinate. のstructure-activity relationship study showed that oxidation of Pyxinol at the C-12 position can effectively improve the anti-inflammatory activity of derivatives modified at the C-3 position. In particular, N-Boc-protected aromatic amino acids can significantly enhance their anti-inflammatory activity. At the same time, derivatives with the absolute configuration of R at the C-24 position are more active.

Wang etアル[41] used a similar method to selectively oxidize the C-3 position of the Pyxinol skeleton のring and simultaneously introduce a Michael acceptor to prepare 24 novel ginsenoside derivatives (67a-67h, 68a-68h, 69a-69h) (see Figure 10). The structure-activity relationship shows that the fusion of ginsenoside PPD with a Michael acceptor can enhance the anti-inflammatory activity of the derivative, and the presence of an electron-withdrawing group on the Michael acceptor further enhances the anti-inflammatory activity. The anti-inflammatory activity of the derivative obtained by modifying the C-20 position of PPD with a tetrahydrofuran ring was greatly reduced, but the anti-inflammatory activity of the derivative in which the A ring was oxidized was almost unaffected, which further indicates that the anti-inflammatory biological activity of some ginsenosides can be significantly improved by oxidation modification.

Zhang etアル[42] hydrolyzed PD and oxidized it using pyridinechlorochromate (PCC), O2, and H2O2 to obtain a series of C-17 side chain and A and C ring oxidation derivatives (see Figure 11). Antitumor cell tests showed that some compounds exhibited better antiproliferative activity than the positive control in six cell lines, including A549 (human lung cancer), 8901 (human ovarian cancer), and other cell lines. For example, in the U87 (human glioma) cell line, compounds 70, 78, 82 and 83 were more effective than the positive control, with compound 82 having an IC50 of 19.51±1.00 μmol/L. In the MCF-7 (human breast cancer) cell line, compared with 5-fluorouracil and PD, compounds 71 and 82 exhibited better antitumor activity (IC50 = 17.73~23.58 μmol/L); compounds 71 and 74 also exhibited good antiproliferative activity in HeLa cells. Studies have shown that introducing an enol structure at the α-site of the A ring of PD derivatives can improve their antitumor activity, but not all oxidative modifications of PD derivatives achieve this effect. For example, the antiproliferative activity of compound 81, which was obtained by further oxidation with H2O2, was reduced.

2.3 Heterocyclic修正

Heterocyclic compounds are often used in drug design and synthesis because of their structural diversity and wide range of biological activities, which provides an expansion of the available space for drug-like chemistry. Most marketed drugs contain heterocyclicstructures, with nitrogen heterocycles being the most common in marketed drug structures. The nitrogen heterocycles and oxygen heterocycles commonly found in drug molecules contain lone pairs of electrons, which can form hydrogen bonds, which is conducive to improving water solubility and thus bioavailability. Piperazine rings and piperidine rings are very common nitrogen heterocyclic structures in marketed drugs. They can be further derivatized to establish a small compound library [43], which is conducive to designing more compounds for in-depth structure-activity relationship studies. Studies have shown that the introduction of heterocycles in natural products can greatly enhance the biological activity and solubility of derivatives through the principle of “pharmacophore combination” and an increase in the number of hydrogen bonds [44-45]. At present, a large number of studies have reported on the modification of ginsenoside derivatives with heterocycles. Among them, nitrogen-containing heterocyclic compounds have low cytotoxicity, and exhibit good water solubility, permeability and bioavailability.

Pyrazoles are five-membered heterocyclic compounds composed of two adjacent nitrogen atoms. They have a variety of pharmacological activities such as anti-inflammatory, antiviral and antidepressant effects, and are widely used in new drug development [46]. Isoxazole derivatives also have a variety of biological activities such as 抗菌, antiviral and antitumor effects, and are widely used in organic synthesis [47]. Based on this, Dai etアル[48] introduced the pyrazole and isoxazole skeletons into the C-3 position of PD, designed and synthesized 19 PD derivatives containing heterocycles (see Figure 12), and studied their antiproliferative activities against four different tumor cells. The results showed that the products 86 and 87 obtained by fusing the A ring of PD with the pyrazole ring have significant anti-cancer activity. For example, 86 has an IC50 of 14.15±1.13 μmol/L against HepG-2 cells, and 87 has an IC50 of 13.44±1.23 μmol/L against A549, which is four times that of PD. It also has a greater inhibitory effect on the other three tumor cells. However, compounds 88 and 89a–89i have 貧しいwater solubility due to the presence of multiple ester bonds and hydrophobic groups such as aromatic rings, resulting in poor anti-tumor proliferation activity. Substituting the ester bonds in the structures of derivatives 88 and 89a–89i with amide bonds to obtain derivatives 90a–90f did not improve the anti-tumor proliferation activity. On the other hand, the results of in vitro activity tests showed that 87 > 86, 89a > 88, and 90a > 91, which indicates that pyrazole-modified PD derivatives are generally more 活躍than isoxazole compounds.

ピラジンおよびピリミジン化合物は幅広い生物活性を示し、これら2種類の構造は市販されている薬剤分子によく見られる[49-50]。wangら[51]導入ピラジン、オキサジアゾール、イソオキサゾール、ピラゾール、ピリミジンなどの複素環式化合物は、酸化、水素化、クレゼンエステル縮合、還元、水酸基の保護および脱保護などの古典的な有機反応を介してppdのc-2位およびc-3位に導入された。一連のheterocyclic融合20 (S) -PPD派生商品説明される(図13を参照)および抑制効果を受容体押しB核要因-κアグリコン(RANKL) -induced破骨細胞分化を评価します。structure-activity関係】PPDに比べ、派生商品をphenylpyrazoleに加えて、抑制をチューニング微分破骨細胞のアプリケーションoxadiazole、isoxazoleとpyrazole派生商品five-membered heterocyclic修正(93、94、95 a)は強くよく似またはちょっと抑制活動(IC50 = 103μmol / L) PPDよりピラジンやピリミジン(92,96a)のような6員環複素環で修飾された化合物の阻害活性は有意に増加する。

Based on the excellent activity of compound 96a, the research group further modified the pyrimidine derivatives (see Figure 14). The results showed that at a moderate concentration of 1.0 μmol/L, most derivatives had almost 100% inhibitory effect (except 96f); at a concentration of 0.1 μmol/L, the inhibition effect of the methyl (96b) and ethyl (96c) modified derivatives was significantly enhanced, while the inhibition activity of the methoxy (96d), ethoxy (96e) and amino (96g) modified compounds remained almost unchanged. The researchers further structurally modified 96b with a C-12-hydroxy or C-17 side chain (see Figure 14). The results showed that replacing the hydroxyl group at the C-12 position with a ketone (98), oxime (99), α-hydroxy (100) or acetate (101) group resulted in a significant decrease in inhibitory activity. At a concentration of 0.01 μmol/L, 98–101 showed almost no inhibitory effect. Compound 105 showed the best inhibitory activity (IC50 = 11.8 nmol/L), even at a concentration of 0.01 μmol/L, which was better than PPD activity (IC50 = 10.3 μmol/L), and it could inhibit osteoclastogenesis both in vitro and in vivo.

2.4ポリマー修正

Hydrophilic polymer-modified anticancer drugs can not only compensate for their poor targeting, but also improve the water solubility, stability, in volume vivohalf-life and bioavailability of the drug [52]. In recent years, drug delivery technology has developed rapidly, making ginsenosides widely studied. Lu etアル[53] prepared Rh2 conjugateswith water-soluble O-carboxymethyl chitosan (O-CMC) (Rh2-conjugated O-CMCO-CMC/Rh2) (106) (see Figure 15) via an esterification reaction.  その結果、106は非常に多孔質であり、構造中のエステル結合はph感受性であることが示された。ph 5.8では初期の方がrh2の放出速度が速いため、炎症性疼痛時の損傷部位のph変化に応じてrh2の放出速度を制御することができた。o-カルボキシメチルキトサンの共役は、生体内でのrh2の溶解度を高め、放出速度を調節し、体内での作用持続時間を延長することによって、生物学的有効性を高めた。これにより、生体内でのrh2の生物学的有効性が向上します。

Polyethylene glycol (PEG) has the advantages of being easy to modify, biodegradable, biocompatible and having a high drug encapsulation rate, and thus shows great promise in drug delivery. Mathiyalagan etアル[54] combined hydrophilic PEG with hydrophobic Rh1 and Rh2 to synthesize two types of passive targeted delivery ginsenoside derivatives (see Figure 15). Compared with Rh1, PEG-Rh1 (107) has higher antitumor activity in human lung cancer cell lines (A549), while PEG-Rh1 and PEG-Rh2 do not exhibit cytotoxicity in an uninfected murine macrophage cell line (RAW 264.7). Among them, PEG-Rh2 (108) can greatly inhibit nitric oxide production and thus exhibit better anti-inflammatory activity. This indicates that PEG polymers can not only improve the solubility of ginsenosides and reduce cytotoxicity, but also achieve targeted delivery through the enhanced permeability and retention (EPR) effect and different pHconditions.

2.5共役修正

It has been reported that TPP conjugates have strong mitochondrial targeting ability, and have been used to selectively deliver anticancer drugs, including adriamycin and cisplatin, to the mitochondria of tumor cells [55]. In order to improve the targeting and activity of ginsenoside 25-MeO-PPD, 25-OH-PPD and PD, Ma et al. [56] introduced alkyl chains of different lengths at their C-3 positions, and then conjugated triphenylphosphine (TPP) at the end to synthesize a series of ginsenoside conjugates (see Figure 16). Anti-proliferation studies on cancer cell lines (A549, MCF-7) and normal cells (GES-1) showed that most of the conjugates were more active than the corresponding parent compounds, and exhibited stronger inhibitory effects in cancer cells than in normal cells. Among them, 109 can accumulate in the mitochondria of MCF-7 cells, stimulate the production of reactive oxygen species (ROS), and cause depolarization of the mitochondrial membrane potential, leading to apoptosis. Therefore, 109 exhibits high selectivity and a good antiproliferative effect (IC50 = 0.76 μmol/L) on MCF-7 cells.

2.6他の修正

In addition to the five methods mentioned above, structural modifications of ginsenosides also include etherification, alkylation, catalytic hydrogenation, and glycosylation [57-58]. Etherification and alkylation involve the reaction of the hydroxyl group of ginsenosides with haloalkanes under the catalysis of alkalis. Catalytic hydrogenation involves the use of a catalyst to directly hydrogenate the unsaturated group in the monomeric structure of ginsenosides to a saturated group. Glycosylation involves the introduction of corresponding donor groups such as mannosyl, xylosyl and rhamnosyl groups into the hydroxyl group of ginsenosides. For example, Ren et al. [59] introduced sugar donors to the C-20 OH of PPD derivatives through oxidation, reduction, nucleophilic substitution, and other reactions to prepare a series of ginsenoside C-K derivatives with different sugar rings [60-65].

3概要

This paper reviews the structural modification methods of ginsenosides in recent years. It mainly uses organic acids, amino acids and inorganic acids to react with the hydroxyl groups at the C-3 and C-20 positions of the aglycone and the primary hydroxyl groups on the sugar chain of ginsenosides to obtain ester derivatives, in order to improve the lipid solubility and bioavailability of ginsenosides. Studies on structure-activity relationships have shown that the activity of ginsenoside derivatives after esterification modification has the following characteristics: unsaturated fatty acids > saturated fatty acids, short-chain fatty acids > long-chain fatty acids. Sulphate modification by introducing polar groups, oxidation modification by reducing unsaturation or adding ionizable groups such as carboxyl groups, heterocyclic modification by increasing the number of hydrogen bonds, and hydrophilic complex modification can all improve the water solubility and bioavailability of ginsenosides to varying degrees, and can significantly improve the biological activity of these derivatives. These modification methods provide an important reference for the study and development and ginsenosidesの応用.

However, there are currently some deficiencies in the structural modification of ginsenosides: firstly, there are relatively few structural modification methods. Structural modification mainly involves introducing groups that can react with hydroxyl groups, making the sites and types of products of structural modification relatively simple, and leading to insufficient research on the structure-activity relationship. In particular, there is a relative lack of modification of the sugar chain. There are few reports on the replacement of the sugar chain and the splicing of the sugar chain essential for activity with other different types of aglycon or skeleton to enhance activity and broaden the scope of activity. Second, the lack of precision in structural modification results in low activity. Current research on the activity of ginsenoside derivatives mainly focuses on in vitro anti-tumor and anti-oxidant activities, and there is relatively little further research on in vivo activity, with very few compounds entering clinical research. Third, the research on the activity of ginsenoside derivatives is not in-depth enough. There is very limited research on ginsenosides and their derivatives with immunostimulatory activity as vaccine adjuvants. The few studies on ginsenoside adjuvants mainly use crude ginsenoside extracts, and there is a lack of systematic research on the potential application value of ginsenosides and their derivatives as potent immunostimulants in vaccine adjuvants.

Fourth, current structural modifications mainly focus on dammarane-type ginsenosides, with relatively few modifications to oleanolic acid and orcinol-type ginsenosides. Therefore, future structural modifications should improve the accuracy of introducing groups and structures, expand structural modification methods and modification sites, expand the application scope of ginsenoside derivatives, and lay a theoretical foundation for the development of ginsenoside drugs and health foods.

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