Ginsenoside
Ginsenosides are a diverse class of triterpene saponins, primarily of the dammarane type, that serve as the main pharmacologically active compounds in ginseng plants of the genus Panax, such as Panax ginseng (Asian ginseng) and Panax quinquefolius (American ginseng). These steroid glycosides, first isolated in 1963, consist of a triterpenoid aglycone backbone attached to one or more sugar moieties, with over 270 distinct structures identified as of 2024,[1] commonly classified into protopanaxadiol (e.g., Rb1, Rb2, Rg3) and protopanaxatriol (e.g., Rg1, Re) groups based on their aglycone types. Found predominantly in the roots but also in other plant parts like leaves and fruits, ginsenoside content varies by species, plant age (peaking around 6 years), cultivation method, harvest season, and processing techniques, such as steaming to produce red ginseng, which enhances certain bioactive forms.[2][3] Ginsenosides have been central to the traditional use of ginseng in Chinese medicine for over 2,000 years, where the herb is valued for its adaptogenic properties to promote vitality and resilience to stress. Pharmacologically, they exhibit a broad spectrum of effects through multi-target mechanisms, including modulation of steroid hormone receptors (e.g., glucocorticoid and estrogen receptors), enhancement of antioxidant defenses, and regulation of signaling pathways like PI3K/Akt and NF-κB. Notable activities encompass neuroprotection against oxidative stress and neurodegeneration, anti-inflammatory effects by inhibiting pro-inflammatory cytokines, cardiovascular benefits such as improved endothelial function and reduced arrhythmias, antidiabetic actions via glucose metabolism regulation, and anticancer potential through induction of apoptosis and inhibition of tumor angiogenesis.[2][3][4] Their therapeutic promise has spurred extensive research, with ginsenosides increasingly explored as dietary supplements for immune modulation, metabolic health, and anti-aging, though bioavailability challenges—due to poor absorption and rapid metabolism—necessitate formulations like nanoparticles or glycoside hydrolysis for enhanced efficacy. Ongoing studies emphasize their role in veterinary applications for animal health and in biotechnology for microbial production to meet demand, underscoring ginsenosides' significance in both traditional and modern pharmacology.[5][6]Nomenclature and Definition
Etymology and Naming
The term "ginsenoside" is derived from "ginseng," referring to plants of the genus Panax, combined with "saponin" to denote their classification as triterpenoid glycosides that produce soap-like foaming when agitated in water, a characteristic property of saponins.[7] This nomenclature reflects their origin as bioactive compounds primarily isolated from ginseng roots, where they constitute the major secondary metabolites responsible for the plant's pharmacological effects.[8] An alternative designation, "panaxosides," stems from the genus name Panax, coined by Swedish botanist Carl Linnaeus in the 18th century from the Greek word panax (Πάναξ), meaning "all-healing" or "panacea," based on the herb's longstanding use in traditional Chinese medicine as a versatile tonic.[9] The isolation and initial characterization of these compounds as ginsenosides occurred in 1963, with systematic structural studies advancing in the 1960s through research by Japanese scientists led by Sankichi Shibata and Osamu Tanaka, who separated and identified key saponins from Panax ginseng.[2] The conventional naming system for individual ginsenosides uses the prefix "Rg" or similar (with "R" denoting "root"), followed by lowercase letters (such as a, b, c) to group compounds by polarity during chromatographic separation, and Arabic numerals to indicate the order of discovery or elution in thin-layer chromatography.[7] Over 150 distinct ginsenosides have been identified to date, as of 2024, with Rb1 serving as a representative example of the most abundant protopanaxadiol-type compound in ginseng roots.[10][11] As structural elucidations progressed, this empirical system evolved toward standardized International Union of Pure and Applied Chemistry (IUPAC) nomenclature; for instance, ginsenoside Rb1 is formally named 20-[β-D-glucopyranosyl-(1→6)-β-D-glucopyranosyloxy]-12β-hydroxydammar-24-en-3β-yl β-D-glucopyranosyl-(1→2)-β-D-glucopyranoside.Chemical Definition
Ginsenosides are a class of natural product steroid glycosides and triterpene saponins found almost exclusively in species of the Panax genus, such as Panax ginseng and Panax quinquefolius.[2] These compounds are characterized by their amphiphilic nature, arising from a hydrophobic triterpenoid aglycone core combined with hydrophilic sugar chains attached via glycosidic bonds.[2] This structural duality contributes to their role as surface-active agents in plant tissues.[12] The general chemical formula of ginsenosides involves a dammarane-type triterpenoid aglycone—a tetracyclic structure derived from dammarenediol—as the backbone, covalently linked to one or more monosaccharide units (such as glucose or rhamnose) through ether-type glycosidic linkages.[13] Molecular weights of these glycosides typically range from 800 to 1200 Da, depending on the number and type of sugar moieties.[13] Key physical properties of ginsenosides include a characteristic bitter taste, which serves as an antifeedant in plants, and the ability to produce stable foams when agitated in water, a hallmark of their saponin classification.[12] They exhibit poor solubility in water, though glycosylation enhances their hydrophilicity compared to the non-glycosylated aglycones, and they are more readily soluble in polar organic solvents like methanol.[2] For analytical detection, ginsenosides show strong UV absorption at approximately 203 nm due to the π-π* transitions in their aglycone chromophores.[14] Ginsenosides are distinguished from other saponins by their exclusive occurrence in ginseng species and their predominant dammarane-based triterpenoid skeletons, in contrast to the steroidal (C27) frameworks of saponins from plants like those in the Liliaceae family.[13]Structural Classification
Aglycone Types
Ginsenosides are primarily classified into three main aglycone types based on their core triterpene skeletons: dammarane (the most common, comprising over 90% of known ginsenosides), oleanane, and ocotillol.[3][15] The dammarane type dominates in species like Panax ginseng and Panax notoginseng, while oleanane and ocotillol types are less prevalent overall.[16] These aglycones serve as the hydrophobic cores that are subsequently modified by glycosylation to yield the full ginsenoside structures.[17] The dammarane-type aglycones, derived from the cyclization of 2,3-oxidosqualene, feature a tetracyclic structure with 17 carbon atoms in the ring system and a side chain at C-17.[18] They are further subdivided into protopanaxadiol (PPD) and protopanaxatriol (PPT) subtypes. PPD aglycones, such as that in ginsenoside Rb1, possess hydroxyl groups at C-3, C-12, and C-20, with the molecular formula \ce{C30H52O3}.[19] PPT aglycones, exemplified by that in ginsenoside Rg1, include an additional hydroxyl at C-6, resulting in the formula \ce{C30H52O4}.[20] Stereochemistry at C-20 is typically 20S in naturally occurring forms, though 20R epimers can arise as artifacts during extraction or processing.[21] Oleanane-type aglycones exhibit a pentacyclic triterpene structure akin to oleanolic acid, characterized by a double bond between C-12 and C-13 and a carboxylic acid group at C-28.[22] A representative example is the aglycone of ginsenoside Ro, which maintains this configuration and is found in lower abundance compared to dammarane types.[15] Ocotillol-type aglycones are rare, constituting less than 1% of ginsenosides in Panax ginseng, and consist of a tetraoxygenated dammarane skeleton featuring a tetrahydrofuran ring at C-20.[23] An example is the aglycone in majonoside-R2, which includes oxygenations at C-20, C-24, and other positions, distinguishing it from standard dammarane subtypes.[15]Glycosylation Patterns
Ginsenosides are characterized by their glycosylation at specific positions on the aglycone backbone, primarily through β-glycosidic bonds that link sugar moieties, resulting in mono-, di-, or trisaccharide chains. These attachments occur mainly at C-3 for protopanaxadiol (PPD) and protopanaxatriol (PPT) types as well as oleanane types, at C-6 for PPT types, and at C-20 for all dammarane-based ginsenosides (PPD and PPT).[24][17] The common sugars involved include β-D-glucose (Glc), α-L-rhamnose (Rha), α-L-arabinose (Ara in pyranosyl or furanosyl forms), β-D-xylose (Xyl), and β-D-glucuronic acid (GlcA), which are attached via specific linkages such as (1→2), (1→6), or (1→4).[25][2] In PPD-type ginsenosides, glycosylation typically features glucose chains at C-3 and C-20, contributing to their classification within the Rb, Rc, and Rd groups. For instance, ginsenoside Rb1 exhibits a disaccharide at C-3 [β-D-Glc-(1→2)-β-D-Glc] and a monosaccharide at C-20 [β-D-Glc], enhancing its structural diversity within this subclass.[24] PPT-type ginsenosides extend this pattern by incorporating an additional sugar at C-6, often a glucose-rhamnose combination, as seen in ginsenoside Re with β-D-Glc-(1→2)-α-L-Rha at C-6 and β-D-Glc at C-20, distinguishing the Rg and Re groups.[17][25] Oleanane-type ginsenosides, such as Ro, are primarily glycosylated at C-3 with a glucuronic acid-arabinose disaccharide [β-D-GlcA-(1→2)-β-D-Ara(p)], lacking the C-20 modification common in dammarane types.[2][24] These glycosylation variations generate over 270 known ginsenoside variants through combinatorial attachments as of 2024, with the number and complexity of sugar chains directly influencing polarity—more extensive glycosylation, as in the Rb group with multiple glucoses, increases hydrophilicity compared to less substituted forms like the Rg group.[17][24][1] This polarity gradient affects solubility and separation in analytical contexts, underpinning the structural subclassification of ginsenosides.[25] Rare modifications, such as acetylation on sugar hydroxyl groups (e.g., in the Rs series like Rs1 with an acetyl group at the C-20 glucose) or sulfation in certain Panax species, further diversify patterns but occur infrequently.[2][24]| Ginsenoside Type | Example | Glycosylation at Key Sites | Sugars and Linkages |
|---|---|---|---|
| PPD | Rb1 | C-3: disaccharide; C-20: monosaccharide | β-D-Glc-(1→2)-β-D-Glc at C-3; β-D-Glc at C-20[24] |
| PPT | Re | C-6: disaccharide; C-20: monosaccharide | β-D-Glc-(1→2)-α-L-Rha at C-6; β-D-Glc at C-20[17] |
| Oleanane | Ro | C-3: disaccharide | β-D-GlcA-(1→2)-β-D-Ara(p) at C-3[2] |