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MindMap Gallery Natural medicinal chemistry Steroids and their glycosides
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Natural medicinal chemistry Steroids and their glycosides
This is a mind map about natural medicinal chemistry steroids and their glycosides, including an overview of steroids, C21 steroids, cardiac glycosides, steroidal saponins, etc.
Edited at 2024-01-16 20:38:04
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Natural medicinal chemistry Steroids and their glycosides
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- Outline
Steroids and their glycosides
Overview of steroids
Definition: Products derived from cyclopentane polyhydrophenanthrene as the parent nucleus
Classification: Classified according to the fusion method of the mother core and the different side chains of C17
biosynthetic pathways
From a biogenic point of view, steroid components are all converted through the biosynthetic pathway of mevaleric acid, often with -OH, -OCH3, and -CH3 substitutions. However, which of triterpenes and sterols is the precursor has not yet been determined. Conclusion
Structural features
Most of the side chains at positions C10, C13 and C17 of natural steroids are in β-configuration. According to the spatial arrangement of the hydroxyl group at the C3 position, it has two isomers, namely β-type and α-type. Functional groups such as hydroxyl, carbonyl, and double-bonded epoxy ether bonds can also be substituted on the steroid core.
chemical properties
Under anhydrous conditions, various color reactions can occur when encountering acid.
Liebermann-Burchard reaction (acetic anhydride-concentrated sulfuric acid): (green, distinguished from triterpenes, triterpenes purple)
Salkowski reaction (chloroform-concentrated sulfuric acid reaction): the chloroform layer shows blood red or cyan, and the sulfuric acid layer shows green fluorescence
Rosen-Heimer reaction: sample + 25% trichloroacetic acid/ethanol solution, appears red at 60°C (different from triterpene saponins, appears red at 100°C)
Antimony trichloride or antimony pentachloride reaction
C21 steroids
Definition: A class of steroid derivatives containing 21 carbon atoms, mostly with double bonds at the 5 and 6-positions, with anti-inflammatory, anti-tumor, anti-fertility and other biological activities
Classification: There are two main structural types: cortisol and cortisone
Structural features
In addition to existing as free bodies, C21 steroid components can also exist in the form of glycosides. The types of sugars include 2-OH sugar or 2-deoxy sugar, 6-deoxy sugar, 2,6-dideoxy sugar, etc.
cardiac glycosides
Definition: It is a steroidal glycoside compound found in plants that has cardiotonic effects.
Classification
Classification according to the type of unsaturated lactone with C17 side chain: • The unsaturated lactone with a five-membered ring is called alpha cardiac aglycone; the position of the sugar attached to the alpha cardiac glycoside mother core is position 3 • An unsaturated lactone with a six-membered ring called beta cardiac aglycone The above two cardiac glycosides belong to the β-configuration (some are α-configuration, and the naming time is marked with 17β-H)
name
Alpha cardiac glycosides are named after cardiac steroids as their parent nucleus. Such as: digitoxigenin; B-type cardiac aglycone has sulfonate or bufoxin as the mother core, such as: scallion aglycone
Types of sugar
Six-carbon aldose, five-carbon aldose, 6-deoxysugar, 6-deoxysugar methyl ether; and 2, 6-dideoxysugar, 2, 6-dideoxysugar methyl ether
Cardiac glycosides can be divided into three types according to the type of connecting sugar • Type I: aglycon-(2,6-dideoxysugar)X-(glucose)Y • Type II: aglycon-(6-deoxysugar)X-(glucose)Y • Type III: aglycon-(glucose)X • Type I and II are more common, type III is less common
Physical and chemical properties
General properties
Shape and solubility
Mostly colorless crystals or amorphous powders. The glycoside is soluble in water, acetone, alcohol and other polar solvents, and slightly soluble in ethyl acetate. The aglycone is easily soluble in benzene, ether and chloroform.
Lactone properties
Due to the presence of a lactone ring in the structure, it can be ring-opened in aqueous solutions of NaOH or KOH and reduced when exposed to acid; however, in alkali alcohol solutions, the ester ring isomerizes and cannot be restored when exposed to acid.
hydrolysis of glycoside bonds
acid hydrolysis
mild acid hydrolysis
Type I cardiac glycosides can be hydrolyzed into aglycones and sugars by using dilute acid (0.02-0.05mol/L) hydrochloric acid or sulfuric acid in water-containing alcohol for a short time (half an hour to several hours) to heat and reflux.
It mainly hydrolyzes the glycoside bond between aglycone and α-deoxysugar or the sugar bond between α-deoxysugar and α-deoxysugar.
Strong acid hydrolysis
Using relatively concentrated acid (3%-5%) to heat and reflux for a long time or pressurize at the same time can hydrolyze type II and type III cardiac glycosides and obtain quantitative glucose. Hydrolyzable alpha-hydroxy sugars. However, this method often causes the aglycone to lose one or several molecules of water, forming a dehydrated aglycone, that is, a secondary glycoside. The partial hydrolyzate of saponin sugar chain or the hydrolysis of disaccharide chain saponin into monosaccharide chain saponin are called subsaponins.
Hydrogen chloride acetone method (Mannich method, longer reaction time)
After reacting with hydrogen chloride for a long time at room temperature (about two weeks, the reaction solution contains 0.4-1% HCl), 2-OH and 3-OH in the sugar molecules react with acetone to generate acetonide, which is then hydrolyzed to obtain the original glycoside. Yuan and sugar derivatives.
enzymatic hydrolysis
Plants containing cardiac glycosides have enzymes that hydrolyze glucose but no enzymes that hydrolyze α-deoxysugar, so they can hydrolyze and remove the glucose in the molecule while retaining α-deoxysugar. Snail enzyme can hydrolyze almost all glycoside bonds, and can gradually hydrolyze the sugar of cardiac glycoside molecules until the aglycone is obtained. It is often used to study the structure of cardiac glycosides.
Alkaline hydrolysis
Alkaline reagents mainly hydrolyze the acyl group in the molecule, cleave the lactone ring, translocate Δ20 (22) and isomerize the aglycone, etc.
Color reaction
Reactions that act on the steroid core
Liebermann-burchard reaction Salkowski reaction (chloroform-concentrated sulfuric acid reaction) Antimony trichloride or antimony pentachloride reaction
Acts on lactone ring
Alpha cardiac glycoside undergoes double bond transfer in alkaline alcohol solution to generate active methylene, so it can react with active methylene reagent to develop color.
Acts on 2-deoxysugar
Keller-Kiliani reaction
Cardiac glycoside/Fe3 glacial acetic acid, add concentrated sulfuric acid dropwise, observe the interface and the color change of acetic acid. If 2-deoxysugar is present, the acetic acid layer will gradually turn blue or blue-green. The color of the interface varies with different aglycones. Application objects - free 2-deoxysugar, cardiac glycosides that can hydrolyze 2-deoxysugar (pit: negative cannot mean that there is no 2-deoxysugar, because it may not be able to hydrolyze 2-deoxysugar)
Reaction of p-dimethylaminobenzaldehyde (as color developer)
Gray red; also found in azulines
xanthydrol reaction
Reagent: 10 mg xanthenyl alcohol dissolved in 100 ml glacial acetic acid, add 1 ml concentrated sulfuric acid Sample reagent water bath heated for 3 minutes → red
Periodic acid-p-nitroaniline reaction
Cardiac glycoside, periodic acid, p-nitroaniline→yellow
Spectral characteristics
UV
Mainly for the absorption of unsaturated lactone rings: Alpha cardiac glycoside (Δαβ-γ lactone) at 220 nm Beta cardiac glycoside (αβ; γδ-δ lactone) 295~300nm This can be used to distinguish the second type of cardiac glycosides.
hydrogen spectrum
1) Methyl group at positions C10 and C13 of aglycone δ 1.00 or so 2) C3-H (often substituted by -OH) δ around 3.90 3) Protons on the lactone ring 4) The C/D rings of cardiac glycosides are all cis-fused (14β-H), so δ: 18-CH3 > 19-CH3 (in a higher field). Among other steroid components, it can be determined based on the two A The displacement of the base is used to determine the C/D ring fusion mode.
Physiological activity
Cardiotonic structure: (1) The C/D ring must be cis-fused (2) C-14 position needs to be substituted with -OH (3) Position 17 must be β-configuration unsaturated lactone (4) The sugar part has no cardiotonic effect, but among cardiac glycosides, the nature and number of sugars have an impact on the cardiotonic effect. (5) Glycosides derived from 2, 6-dideoxysugar have stronger affinity for the myocardium and central nervous system than glucosides Potency, cardiotonic activity, toxicity and lipophilicity of this type of glycoside are in a parallel relationship.
Steroidal saponins
Overview
Definition: Steroidal saponins are a type of oligosaccharide composed of spirosteroid compounds combined with sugars.
Distribution: Mainly found in Dioscoreaceae, Liliaceae, Scrophulariaceae, Sarsaparilla, Agaveceae and other plants.
Physiological activity: In the early days, it was used as a raw material for the synthesis of steroidal contraceptives and hormonal drugs; later, new biological activities were gradually discovered, especially the prevention and treatment of cardiovascular and cerebrovascular diseases, anti-tumor, hypoglycemic and immune regulation.
Structural characteristics and classification
Structural features: 1) 27 carbons 2) A/B cis or trans, B/C, C/D cyclic trans 3) C-17 side chain---β configuration 4) E and F rings are connected in the form of spiroketal.
Category: Spirostanols; Isospirostanols; Furostanols; Modified Spirostanols • There are two epimers of the methyl group at C25 position • When the methyl group at position C25 is located on the vertical bond on the plane of the F ring, it is β-oriented, and the absolute configuration is S-type, also known as L-type or neo-type (i.e. 25S, 25L, 25βF, neo) - spirostane • When the C25 methyl group is located on the cross bond under the plane of the F ring, it is α-directed, and the absolute configuration is R type, also known as D type or iso type (i.e. 25R, 25D, 25αF, iso) - isospiral sterane • Furostanols: F-ring-cleaved disaccharide chain saponins do not have the properties of certain saponins 1) No hemolysis 2) Cannot form complex with cholesterol 3) No antibacterial activity • Monosaccharide chain saponins derived from spirostanes have obvious antibacterial activity.
Physical and chemical properties
General properties: Most steroidal sapogenins are in a good crystalline state and can be dissolved in lipophilic solvents such as petroleum ether and chloroform, but are insoluble in water. The melting point often increases as the number of hydroxyl groups increases. When combined with sugars to form glycosides, especially when combined with oligosaccharides to form saponins, aglycones are generally soluble in water, easily soluble in hot water and dilute alcohol, almost insoluble or difficult to dissolve in lipophilic solvents, and are mostly amorphous. powder.
Surface activity and hemolysis: similar to triterpene saponins, but saponins with split F rings often do not have hemolysis and have reduced surface activity
Steroidal saponins form molecular complexes with sterols: 1. Ethanol solutions of steroidal saponins can be precipitated by sterols (commonly cholesterol). 2. The generated molecular complex can be extracted with ether reflux, then cholesterol is soluble in ether, but saponin is insoluble, thereby purifying saponin and checking whether there are saponin components. 3. All sterols containing β-OH at C3 position (such as β-sitosterol, stigmasterol, ergosterol, etc.) can combine with saponins to form insoluble molecular complexes. 4. The molecular complex formed by triterpene saponins and sterols is less stable than steroidal saponins.
Steroidal saponins can form precipitates with basic lead salts or barium salts, but cannot form precipitates with neutral lead salts or barium salts.
Under anhydrous conditions, steroidal saponins can also produce color reactions similar to triterpene saponins when encountering certain acids. It is just the reaction of steroidal saponins with acid anhydride-sulfuric acid (LB reaction), and the final color change is green.
F-ring cleaved disaccharide chain saponins do not have the common properties of certain saponins: Without hemolysis, it cannot form a complex with cholesterol. The disaccharide chain saponin with cleaved F ring can react red with dimethylaminobenzaldehyde hydrochloride reagent (referred to as reagent E), and p-anisaldehyde reagent (referred to as reagent A) will appear yellow. The F-ring closed monosaccharide chain saponins and spirostane-derived sapogenins only show yellow color to reagent A and do not show color to reagent E. The method to distinguish protodiosgenin from diosgenin is hydrochloric acid-p-dimethylaminobenzaldehyde (E reagent).
Spectral characteristics
hydrogen spectrum
Feature 1: There are characteristic peaks of four methyl groups (i.e., methyl groups at positions 18, 19, 21, and 27) in the high field region.
Feature 2: The chemical shift value of 27-CH3 is different due to its different configuration: δ: 25R configuration < 25S configuration (the δ value of 27-CH3 can be used to distinguish 25R and 25S). C16 and C26-H are oxygen and carbon protons, which are in a lower field and are easy to identify. The chemical shift values of other protons are similar and overlap with each other, making it difficult to identify.
Feature 3: The coupling constant is also an important parameter in determining the structure. C5-H is α-H; C4-H δ 5.63 (d, J4, 5=12Hz); J indicates that C4-H and C5-H are trans coupling, that is, C4-H is a vertical bond.
carbon spectrum
(1) All 27 13C characteristic peaks of steroidal saponins can be identified; (2) If the C atom is connected to -OH, its δ value moves 40-45 units downfield; when the hydroxyl group is connected to a sugar to form a glycoside, the δ value of the original 13C continues to move 6-10 units downfield. (3) The δ value of C=C carbon moves downfield to 115-150ppm; the δ value of C=O carbon moves downfield to δ=200ppm; (4) The δ values of C18, C19 and C27 carbon are all lower than 20ppm. (5) C16 carbon has an oxygen atom, and its delta value is 80ppm; (6) Because C22 carbon is connected to two oxygen atoms, its δ value is as low as about 109 ppm.
Extraction and Separation
Solvent method (n-butanol-water extraction, chloroform-methanol-water washing)
Precipitation method: segmented precipitation method, lead salt precipitation method, cholesterol precipitation method (the method that can be used to separate spirostane steroid saponins and furostane saponins is the cholesterol precipitation method)
Extraction method of diosgenin: hydrolysis method
Fermentation
Pharmacological effects
(1) Anti-platelet aggregation effect (2) Blood lipid lowering effect (3) Phosphodiesterase inhibitory effect (Agapanthus) (4) Anti-myocardial blood supply effect (5) Anti-arrhythmic and increasing nutritional blood flow of myocardial cells