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MindMap Gallery Natural medicinal chemistry triterpenes and their glycosides
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Natural medicinal chemistry triterpenes and their glycosides
This is a mind map about natural medicinal chemistry triterpenes and their glycosides. Triterpenes and their glycosides are an important class of natural products with a wide range of pharmacological and biological activities.
Edited at 2024-01-16 20:37:24
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Natural medicinal chemistry triterpenes and their glycosides
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- Outline
Triterpenes and their glycosides
Overview
definition
A 30-carbon terpenoid composed of 6 isoprene units, with the general formula (C5H8)6. It can exist in a free state or in the form of glycosides. Most of its glycoside compounds are soluble in water. After the aqueous solution is shaken, it produces a foam like a soapy water solution, so it is called triterpene saponin. Triterpene saponins mostly have carboxyl groups, so they are also called acidic saponins.
distributed
• Mainly distributed in dicotyledonous plants: Caryophyllaceae, Araliaceae, Fabaceae, Aesculaceae, Polygalaaceae, Campanulaceae and Scrophulariaceae • Major traditional Chinese medicines containing triterpenoids such as ginseng (dammarane type), licorice (oleanan type), Bupleurum, astragalus (cycloatun type), Platycodon, toosendan bark, Alisma, Ganoderma lucidum (woolwort) Fat alkane type), etc. • A small number of triterpenoids also exist in animals, such as lanolin alcohol isolated from lanolin and squalene isolated from shark liver; various types of triterpenoids are also isolated from marine organisms such as sea cucumbers and soft corals. Terpenoids.
Existing form
• Glycones: tetracyclic triterpenes, pentacyclic triterpenes • Common sugars: glucose, galactose, xylose, arabinose, rhamnose, uronic acid, special sugars (such as apiose, acetyl aminosugar, etc.) • Sugar chains: monosaccharide chain, disaccharide chain, trisaccharide chain • Glycoside position: 3, 28 (ester saponin) or other positions -OH • Hyposaponins: products of partial degradation of native glycosides
Biosynthesis
Research shows that triterpenes are formed by the cyclization of squalene through different pathways. Squalene is produced by the tail-to-tail condensation of the pyrophosphate ester of the sesquiterpene farnesol.
Tetracyclic triterpenes
Structural features
Tetracyclic triterpenes can be regarded as intermediates from squalene to steroids. Compared with sterol compounds, they have three more methyl groups at positions 4 and 14. They are also considered to be trimethyl derivatives of plant sterols. things.
Tetracyclic triterpenes all have a structural core of cyclopentane and polyhydrophenanthrene. A/B, B/C and C/D rings are all trans-coupled
Structure type (you will be asked to draw the structure and number, which is related to the spectrum)
Dammarane type
Compared with lanolin: Dammarane type: CH3-18 moves from position 13 to position 8; ginsenosides
Using HCl solution for hydrolysis, native sapogenin cannot be obtained in the hydrolyzate. The structure changes, that is, the methyl and hydroxyl groups at position 20 of 20(S)-protopanaxadiol or 20(S)-protopanaxatriol undergo epimerization and transform into 20(R)-protopanaxadiol. Or 20(R)-protopanaxatriol, and then cyclized to form pananaxadiol or panaxatriol.
Lanolin type
Ganoderma lucidum: the dried fruiting bodies of the Polyporaceae fungi Ganoderma lucidum and Purple Zhizhi • Precious Chinese medicinal materials that can replenish vital energy, strengthen the body, nourish and strengthen the body • More than one hundred kinds of tetracyclic triterpenoids are isolated from it, which are highly oxidized lanolin derivatives.
cycloartane type
Compared with lanolin: cycloartane type: CH3-19 is dehydrogenated with 9-position to form a three-membered ring; astragalus saponin
Mansuiane type
Compared with the lanolin alkane structure, the tetracyclic triterpene structure of mannitane type: the methyl groups at positions 13 and 14 are opposite, and C-20 has an α side chain (20S)
Cucurbitane type
Comparison of cucurbitane type and lanolin alkane type: CH3-19 moves from position 10 to position 9; Cholesterol
Azadirachtin type
Neem type consists of 26 carbons, also known as tetranortriterpene; CH3 at position 14 of mansane migrates to position 8
NMR signature data
• Tetracyclic triterpenes generally exhibit 8 methyl signals, of which 5 are unimodal methyl groups and 3 are bimodal methyl groups. • Generally, the methyl signal is between δ 0.62-1.50 • In 13C-NMR, the e-bonded methyl group is shifted downfield relative to the a-bonded methyl group. Generally speaking, a-bond CH3 is between 8.0-20.0, while e-bond CH3 is between 27.5-33.7.
Pentacyclic triterpenes
Oleanane type (β-amelane type)
• The A/B, B/C and C/D rings are in trans form, while the D/E rings are mostly in cis form, and may also be arranged in trans form. • C-3 is substituted by -OH; C-28-CH3 is easily oxidized to acid or CH2OH; 12-13 positions are often dehydrogenated to form an alkene double bond
Oleanolic acid: clinically used to treat hepatitis; glycyrrhizic acid and glycyrrhetinic acid: both have adrenocorticotropic hormone (ACTH)-like biological activity and are clinically used as anti-inflammatory drugs and used in the treatment of gastric ulcers; saikosaponin , Saikosaponin; Phytolactin, Phytolacca saponin; Polygala saponin; Albizia Julibrissin
Ursane type (α-aminal resin type)
Centella Asiatica: has wound healing effect
Lupine type
The E ring is a five-membered carbocyclic ring, and there is an α-oriented isopropyl group substituted on the E ring (C19 position); all rings/rings are trans
Betulinic acid, betulin
suberane type
Suberane is biologically derived from oleanene through methyl shift.
Tripterygium wilfordii
Physicochemical properties of triterpenes and their saponins
physical properties
Properties: Most of the aglycones have good crystal forms, and after forming the glycosides, they are difficult to crystallize and are mostly amorphous powders. It has a bitter and pungent taste and is highly irritating to human mucous membranes.
Solubility: Aglycon is soluble in organic solvents. Glycosides are soluble in water, easily soluble in hot water, dilute alcohol and ethanol. It has good solubility in aqueous butanol and amyl alcohol, and total saponins can be extracted based on this property.
Reduce the surface tension of aqueous solutions
The aqueous solution can produce persistent foam (more than 15 minutes) after shaking, similar to soap, so it is called saponin. Can be used as a detergent and emulsifier. But it is not saponin that produces foam. Mucus and protein can also produce foam, but it is not long-lasting and disappears quickly. The surface activity of saponins is related to the ratio of hydrophilic and lipophilic structures in the molecule. If the ratio is inappropriate, it will not show this property.
Hemolysis
Most aqueous solutions of saponins can destroy red blood cells and have hemolysis, so saponins are often called saponins. Intramuscular injection of saponin aqueous solution can easily cause tissue necrosis, but oral administration has no hemolytic effect, which may be related to its difficulty in being absorbed in the digestive tract. The hemolytic effect of saponins can be expressed by the hemolysis index, which refers to the lowest concentration that can completely dissolve red blood cells in the blood under certain conditions.
The reason for saponin hemolysis is that most saponins can combine with cholesterol in the cell wall to form a water-insoluble molecular complex, which affects the transport function of the cell wall and causes cell rupture. Not all saponins have hemolytic effects. For example, ginsenosides with panaxatriol and oleanolic acid as aglycones have significant hemolytic effects, but ginsenosides with panaxadiol as aglycones have anti-hemolytic effects, so ginseng Total saponins have no hemolytic effect.
The relationship between hemolysis and structure: 1) Triterpenoid saponins that have a polar group on the A ring and a medium polar group on the D or E ring generally have hemolytic effects. 2) When the aglycone has β-OH at position 3 and α-OH or =O at position 16, the hemolysis index is the highest. 3) If the D ring or E ring has a polar group, and a sugar chain is connected to position 28, or a certain number of hydroxyl groups are substituted, the hemolysis effect will disappear. 4) Most monosaccharide chain saponins have obvious hemolytic effect, while disaccharide chain saponins have no hemolytic effect.
Glucose has the effect of stabilizing blood cells, so if it is an injection, saponin can be used together with glucose.
chemical properties
Color reaction
Triterpenoids are produced under anhydrous conditions by reacting with strong acids (sulfuric acid, phosphoric acid, perchloric acid), moderately strong acids (trichloroacetic acid) or Lewis acids (zinc chloride, aluminum trichloride, antimony trichloride). color or fluorescence. Mainly, the hydroxyl group is dehydrated, the double bond is displaced and condensed, and a cationic salt is formed to produce color. Fully saturated ones with no hydroxyl or carbonyl group at the 3-position are negative. Reactions with conjugated double bonds are faster and reactions with isolated double bonds are slower.
Acetic anhydride-concentrated sulfuric acid reaction (Liebermann-Burchard): Produce yellow-red-purple-blue colors Those that turn purple are triterpene saponins; those that turn green are steroidal saponins.
Antimony pentachloride reaction (Kahlenberg reaction): At 60-70℃, blue, gray-blue, gray-purple, etc. are produced. (Antimony trichloride can be used instead of antimony pentachloride, and the reaction results will be the same)
Trichloroacetic acid reaction (Rosen-Heimer reaction): Can be used as a chromatographic reagent for saponin paper The red ones at 100°C are triterpene saponins; the red ones at 60°C are steroidal saponins.
Chloroform-concentrated sulfuric acid reaction (Salkowski reaction): The chloroform layer is red or blue and has green fluorescence
Glacial acetic acid-acetyl chloride reaction (Tschugaeff reaction): Appears light red or purplish red
precipitation reaction
Aqueous solutions of saponins can precipitate with some metal salts such as lead salts, barium salts, ketone salts, etc. • Adding ammonium sulfate, lead acetate or other neutral salts to an aqueous solution of acidic saponins (triterpene saponins) will form a precipitate. • The aqueous solution of neutral saponins (steroidal saponins) requires the addition of basic salts such as basic lead acetate or barium hydroxide to form a precipitate. • This property can be used for the extraction and preliminary isolation of saponins. A method that can be used to separate neutral saponins from acidic saponins is neutral lead acetate precipitation.
Extraction and Separation
Extraction and isolation of triterpene saponins
(1) Extract with methanol and ethanol to obtain the total extract. (2) The extract is extracted with petroleum ether, chloroform, ethyl acetate, and n-butanol in sequence. The triterpenes are mainly in the chloroform layer, and then further separated. (3) The extract is extracted with diethyl ether, and the diethyl ether extract is made into methyl esterification product or acetylation with diazomethane, and then separated after the acetylation product is made (it can prevent tailing or high polarity that makes separation difficult). (4) Hydrolyze saponins with acid to obtain total aglycones, and then separate them. (5) Most compounds need to be separated by various chromatographic methods before monomeric compounds can be obtained. The most commonly used is silica gel chromatography.
Extraction and isolation of triterpene saponins
General method of extraction (ether: precipitation; n-butanol)
Refined (macroporous adsorption resin; total saponins in 30-75% alcohol solution; precipitation: ether, pH, cholesterol)
Separation (separation using various normal phase and reversed phase chromatography)
Distribution chromatography is often used for separation using silica gel column chromatography. Commonly used eluents are chloroform-methanol-water, dichloromethane-methanol-water, ethyl acetate-ethanol-water, etc.
Reversed phase column chromatography RP-18, RP-8, RP-2 Commonly used elution solvents: methanol-water; acetonitrile-water It is widely used in practical work; it is mostly detected at the end absorption point (or evaporated light detection)
Sephadex LH-20 column chromatography
HSCCC method (high speed counter current chromatography): It has the advantages of quantitative sample recovery, no dead adsorption, no interaction with the isolate, large sample loading volume, and fast speed.
biological activity
Anti-inflammatory activity: Oleanolic triterpenes have good anti-inflammatory effects: Oleanolic acid: treats hepatitis; Sodium carbenate: anti-ulcer drug; Tripterygium wilfordii: treats rheumatoid arthritis and systemic lupus erythematosus. and nephritis
Anti-tumor activity: Ursolic acid is one of the anti-cancer active ingredients of Prunella vulgaris;
Antibacterial and antiviral activity: Saponins containing oleanolic acid and helexin with a free carboxyl group at C-27 or 28 have strong antifungal activity
Anti-cardiovascular system diseases: Ginsenosides and saikosaponin a can reduce hyperlipidemia. Gynostemma pentaphylla saponin has a significant inhibitory effect on platelet aggregation and experimental thrombosis in rats. The saponins in tea leaves and tea seeds have antihypertensive effects.
Cholesterol-lowering effect: glycyrrhizic acid; saikosaponins a and d
Molluscicidal activity: Ivy C-3 monosaccharide chain saponin
Has anti-fertility effects
Structure Identification
UV spectrum
Isolated double bond: λmax 205～250 nm; weak absorption Heterocyclic conjugated dienes: λmax 240, 250, 260 nm Homocyclic conjugated diene: λmax 280 nm α,β-unsaturated ketone: λmax 242～250 nm 11-oxo, Δ12-oleanene: 18β-H: ~249 nm; 18α-H: ~243 nm
mass spectrometry
EI-MS of Δ12-oleanene: RDA cracking of C ring: A and B ring fragments b; D and E ring fragments a: base peak; a b = M Other fragments: M; b – H, b – H2O, a – COOH, etc.
EI-MS of 11-oxo, Δ12-oleanene: RDA cleavage, Maxwell rearrangement
Soft ionization mass spectrum of saponins: quasi-molecular ion peaks: [M H], [M Na], [M K], etc.; sugar group connection sequence information: losing outer sugar groups one by one
H NMR
Tetracyclic triterpenes contain 8 methyl signals: 5 are single peaks, 3 are double peaks, δH 0.62～1.50 Alkene hydrogen: δH 4.3～6.0: Intracyclic double bond: δH > 5.0; Extracyclic double bond: δH < 5.0 H on oxygenated carbon: δH 3.2～4.0 H connected to Oac carbon: δH 4.0～5.5
NMR carbon spectrum (PPT example!)
Methyl group: steric effect: a bond: δC 8.0～20.0; e bond: δC 27.5～33.7 Pentacyclic triterpenes: determination of double bond position and parent nucleus; determination of hydroxyl position and orientation Glycosylation shift: determines where the sugar is attached Determination of the acetyl group on sugar: α-C displacement to the lower field: δC 0.2~1.6; β-C displacement to the upper field: δC-2.2~3.5
2D-NMR technology
HSQC (HMQC): Attribution of hydrocarbon signals 1H-1H COSY, TOCSY spectrum: determine the connection relationship of the spin system HMBC spectrum: Determine the connection positions between sugar units; sugar and non-sugar moieties