A glycoside is the acetal form of sugars, characterized by the presence of a glycosidic bond between the anomeric carbon and an alkoxy oxygen atom. These compounds are named by replacing the “e” ending of the sugar’s name with “ide.”
For example, a glycoside derived from glucose is referred to as a glucoside, while one derived from galactose is called a galactoside. When using the pyranose or furanose nomenclature, the acetal is termed a pyranoside or a furanoside, respectively. This nomenclature system simplifies the identification and categorization of glycosides based on their sugar source and structural characteristics.
Chemical Aspects
Much of the chemistry of glycosides is detailed in the discussion on glycosidic bonds. For instance, the glycone and aglycone parts can be separated through hydrolysis in the presence of an acidic catalyst and can also be hydrolyzed using alkaline conditions.
Many enzymes play crucial roles in both forming and breaking glycosidic bonds. Some glycoside hydrolases are essential enzymes for cleaving these bonds, while glycosyltransferases are the key synthetic enzymes in nature. Furthermore, genetically modified enzymes known as glycosynthases have been engineered to efficiently form glycosidic bonds.
There are multiple chemical methods to synthesize glycosidic bonds. Fischer glycosidation involves the synthesis of glycosides by reacting unprotected monosaccharides with alcohols, often using alcohol as a solvent, in the presence of a potent acid catalyst. The Koenigs-Knorr reaction, on the other hand, entails the condensation of glycosyl halides and alcohols, facilitated by metal salts like silver carbonate or mercuric oxide. These methods enable the formation of glycosides through chemical synthesis.
General Characteristics
1. Sugar Dependency
Glycosides contain sugars, but their physical, chemical, and therapeutic activities often depend on the aglycon portion. The presence of sugar can aid in the absorption of the glycoside, assisting it in reaching its site of action.
2. Crystalline Nature and Solubility
Glycosides are typically crystalline or amorphous substances that exhibit solubility in water and dilute alcohol but are insoluble in CHCl3 and ether. The aglycon part of glycosides is usually insoluble in nonpolar solvents like C6H6.
3. Hydrolysis Vulnerability
Glycosides are prone to hydrolysis, which can occur through various means, including mineral acids, water, and enzymatic processes. They often exhibit optical activity, with a tendency to be levorotatory.
4. Fehling’s Solution and Beyond
Glycosides do not have the ability to reduce Fehling’s solution until they undergo hydrolysis. Glycosides are believed to play roles in facilitating growth and providing protection to plants. They serve various functions in the physiology and defense mechanisms of plants.
Classification of Glycosides
Glycosides can be categorized based on several criteria, including the glycone, the type of glycosidic bond, and the aglycone.
By Glycone/Presence of Sugar
When the glycone group of a glycoside is glucose, the molecule is termed a glucoside.
If the glycone is fructose, the molecule is referred to as a fructoside.
When the glycone is glucuronic acid, the molecule is known as a glucuronide.
In the body, toxic substances are often conjugated with glucuronic acid to enhance their water solubility, resulting in the formation of glucuronides, which are then excreted. Compounds can also be broadly categorized based on the class of glycone; for instance, glycosides with a disaccharide (biose) glycone are referred to as biocides.
By Type of Glycosidic Bond
Depending on whether the glycosidic bond is oriented “below” or “above” the plane of the cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Certain enzymes, like α-amylase, can hydrolyze only α-linkages, while others, such as emulsin, specifically target β-linkages.
There are four types of linkages present between glycone and aglycone in glycosides:
1. C-Linkage/Glycosidic Bond: This type of linkage is nonhydrolysable by acids or enzymes. It is highly stable and not easily broken down.
2. O-Linkage/Glycosidic Bond: Glycosides can also have oxygen (O) linkages between glycone and aglycone. These bonds can be hydrolyzed under certain conditions.
3. N-Linkage/Glycosidic Bond: Some glycosides have nitrogen (N) linkages between the glycone and aglycone. These bonds can also be hydrolyzed under specific conditions.
4. S-Linkage/Glycosidic Bond: Sulfur (S) linkages can also exist between the glycone and aglycone in certain glycosides. Like O and N linkages, S-linkages can be hydrolyzed under appropriate conditions.
By Aglycone
Glycosides can also be classified based on the chemical nature of the aglycone. This classification is particularly useful in biochemistry and pharmacology. Here are some examples:
Alcoholic Glycosides: These glycosides contain an aglycone derived from alcohol. An example is salicin, which is found in the Salix genus and is converted in the body into salicylic acid. Salicylic acid has analgesic, antipyretic, and anti-inflammatory effects.
Anthraquinone Glycosides: These glycosides have an aglycone group derived from anthraquinone. They are known for their laxative effects and are mainly found in dicot plants, except for the Liliaceae family, which are monocots. Examples include compounds found in senna, rhubarb, and Aloe species.
Coumarin Glycosides: In this category, the aglycone is coumarin or a derivative thereof. An example is apterin, which can dilate coronary arteries and block calcium channels. Other coumarin glycosides are obtained from dried leaves of plants like Psoralea corylifolia.
Chromone Glycosides: The aglycone part is referred to as benzo-gamma-pyrone.
Cyanogenic glycosides
Cyanogenic glycosides, such as amygdalin, have an aglycone that includes a cyanohydrin group. These compounds are stored by plants in the vacuole, where they remain inactive. However, if the plant is subjected to attack or damage, these glycosides are released and activated by enzymes in the cytoplasm. These enzymes remove the sugar component of the molecule, leading to the collapse of the cyanohydrin structure and the release of toxic hydrogen cyanide.
The storage of cyanogenic glycosides in an inactive form in the vacuole is a protective mechanism to prevent them from causing harm to the plant under normal conditions.
Cyanogenic glycosides serve various functions in plants, and in addition to deterring herbivores, they play roles in regulating germination, bud formation, carbon and nitrogen transport, and potentially act as antioxidants. The production of cyanogenic glycosides is an evolutionarily conserved trait, appearing in species as ancient as ferns and as recent as angiosperms.
Approximately 3,000 species of plants produce these compounds. While they are found in about 11% of cultivated plants in screens, they are present in only 5% of plants overall. It appears that humans have selectively favored plants that produce cyanogenic glycosides.
Examples of plants that produce cyanogenic glycosides include the bitter almond tree, which produces amygdalin and prunasin. Other species that synthesize these compounds include sorghum (the source of the first identified cyanogenic glycoside, dhurrin), barley, flax, white clover, and cassava, which produces linamarin and lotaustralin.
Notably, amygdalin and a synthetic derivative called laetrile were once investigated as potential cancer treatments and were promoted in alternative medicine. However, they have been found to be both ineffective and dangerous.
In some cases, certain butterfly species, such as Dryas iulia and Parnassius smintheus, have evolved to use the cyanogenic glycosides found in their host plants as a form of protection against predators due to their unpalatability.
Flavonoid Glycosides
In this category of glycosides, the aglycone is a flavonoid. There are several examples within this group, including:
Hesperidin: where the Aglycone part is hesperetin and the Glycone part is rutinose
Naringin: where the Aglycone part is naringenin and the Glycone part is rutinose
Similarly;
Rutin: Aglycone: quercetin, Glycone: rutinose
Quercitrin: Aglycone: quercetin, Glycone: rhamnose
Flavonoid glycosides are known for their antioxidant effects and their ability to reduce capillary fragility, making them important for vascular health.
Phenolic Glycosides
In this category, the aglycone consists of a simple phenolic structure. An example is arbutin, which is found in the Common Bearberry (Arctostaphylos uva-ursi). Arbutin is known for its urinary antiseptic effects and is used for its potential benefits in urinary tract health.
Saponins
Saponins are a class of compounds that exhibit a unique property of producing permanent froth when shaken with water. They are also known to cause hemolysis of red blood cells. Saponin glycosides can be found in liquorice and have medicinal value due to their expectorant, corticoid, and anti-inflammatory effects.
Steroid saponins, such as diosgenin found in Dioscorea wild yam, are essential starting materials for the production of semi-synthetic glucocorticoids and other steroid hormones like progesterone.
Ginsenosides, which are triterpene glycosides, are found in Panax ginseng (Chinese ginseng) and Panax quinquefolius (American ginseng).
It’s worth noting that the use of the term “saponin” in organic chemistry can be discouraged because many plant constituents can produce foam, and several triterpene-glycosides can act as surfactants under certain conditions.
In biotechnology, saponins are used as adjuvants in vaccines, such as Quil A and its derivative QS-21, which are derived from the bark of Quillaja Saponaria Molina. These adjuvants stimulate specific immune responses and cytotoxic T-lymphocytes, making them valuable for subunit vaccines, vaccines against intracellular pathogens, and therapeutic cancer vaccines. However, they can have side effects, including hemolysis.
Additionally, saponins serve as natural ruminal antiprotozoal agents that have the potential to improve ruminal microbial fermentation by reducing ammonia concentrations and methane production in ruminant animals.
Steroid Glycosides (Cardiac Glycosides)
These glycosides have a steroid nucleus as their aglycone part and are commonly found in plant genera like Digitalis, Scilla, and Strophanthus. They have been historically used in the treatment of heart diseases, particularly congestive heart failure. However, it’s now recognized that their use does not significantly improve survivability in modern medical practice.
Steviol Glycosides
Steviol glycosides are sweet-tasting glycosides found in the Stevia plant, scientifically known as Stevia Rebaudiana Bertoni. These compounds have an extraordinary sweetness level, ranging from 40 to 300 times sweeter than sucrose (table sugar). The two primary steviol glycosides are stevioside and rebaudioside A, and they are utilized as natural sweeteners in many countries.
The aglycone part of these glycosides is steviol, to which glucose or rhamnose-glucose combinations are bound at the ends to create various compounds. These sweet glycosides offer a calorie-free alternative to sugar and are commonly used as sugar substitutes in food and beverages.
Iridoid Glycosides
These glycosides are characterized by the presence of an iridoid group. Examples include aucubin, geniposidic acid, theviridoside, loganin, and catalpol. Iridoid glycosides have various biological activities and can be found in a range of plant species.
Thioglycosides
Thioglycosides, as the name suggests, contain sulfur in their structure. Examples include sinigrin, which is found in black mustard, and sinalbin, which is found in white mustard. These compounds contribute to the characteristic flavors and properties of these mustard species.
Based on the Therapeutic Nature of Glycoside
Glycosides can also be classified based on their therapeutic properties, and some examples include:
Cardiac Glycosides: Examples include Digitalis, which is used in the treatment of heart conditions.
Laxative Glycosides: Senna is an example of a laxative glycoside used to relieve constipation.
Anti-Ulcer Glycosides: Liquorice contains anti-ulcer glycosides and has been used for its medicinal properties.
Bitter Glycosides: Quassia wood contains bitter glycosides and is known for its bitterness, which can be used for various purposes, including its use as a natural insect repellent and in traditional medicine.
Formation of Glycosides
Similar to the reaction where a hemiacetal reacts with an alcohol to form an acetal, the cyclic hemiacetal formed by a monosaccharide has the potential to react with alcohol, resulting in the formation of two acetals. This chemical process allows for the modification and transformation of sugar molecules into various forms, which has important implications in carbohydrate chemistry and biochemistry.
Mechanism for Glycoside Formation
It’s important to note that when a single anomer reacts with an alcohol, it can lead to the formation of both α-glycosides and β-glycosides. The underlying mechanism of this reaction provides an explanation for the formation of both glycosides.
The mechanism of glycoside formation involves several key steps:
1. The acid protonates the hydroxyl (OH) group bonded to the anomeric carbon of the sugar molecule.
2. A lone pair of electrons on the ring oxygen atom helps facilitate the elimination of a water molecule, resulting in the formation of an oxocarbenium ion. This ion is characterized by a positive charge shared between a carbon atom and an oxygen atom.
3. The anomeric carbon in the oxocarbenium ion is sp2 hybridized, making this part of the molecule planar.
4. When alcohol approaches the planar oxocarbenium ion from the top, it leads to the formation of a β-glycoside. Conversely, when the alcohol approaches from the bottom, an α-glycoside is formed.
N-Glycosides
The reaction of a monosaccharide with an amine is analogous to the reaction of a monosaccharide with an alcohol. In this reaction, the resulting product is known as an N-glycoside. An N-glycoside is characterized by the presence of a nitrogen atom in place of the oxygen typically found in the glycosidic linkage.
It’s important to note that the subunits of DNA and RNA are indeed β-N-glycosides, where the glycosidic linkage connects the nitrogen atom to the sugar. This unique linkage is a fundamental feature of nucleotides and plays a crucial role in the structure and function of these important biomolecules.
Glycoside Hydrolysis
Glycosides are generally stable in neutral or basic conditions and can be isolated and crystallized, making them useful in various chemical reactions and applications. Acetals, which are a type of glycoside, are known for their stability and are commonly employed as protecting groups for aldehydes and ketones in reactions involving strong bases and nucleophiles.
These acetals can be removed by treatment with an acidic solution, allowing them to be hydrolyzed back to cyclic hemiacetals in the presence of acid and water. Just as in the formation of glycosides, the reaction involving acetals can lead to the formation of a mixture of two anomers, contributing to the structural diversity and complexity of these compounds.
The hydrolysis process begins with the protonation of the alkoxy group attached to the anomeric carbon atom. This protonation step is followed by the formation of a planar carbocation intermediate.
Following the planar carbocation intermediate, the hydrolysis process proceeds with a nucleophilic attack by water, followed by a deprotonation step. As a result of these reactions, the two isomers of glucose are formed. It’s worth noting that this mechanism is essentially the reverse of glycoside formation.
In both glycoside formation and hydrolysis, the equilibrium is influenced by the relative excess of the reactants, with the reaction proceeding in the direction dictated by the larger excess of the reactant. This dynamic equilibrium is an essential aspect of these chemical processes.
Isolations of Glycosides
The method used for isolating glycosides is known as the Stas-Otto method. Here’s a description of the procedure:
1. The drug containing the glycoside is finely powdered.
2. The finely powdered drug is subjected to successive extraction in a Soxhlet apparatus, typically using alcohol or a suitable solvent as the extracting agent.
3. After the extraction process, the extract is collected.
4. The collected extract is then treated with lead acetate to precipitate tannins.
5. The mixture is filtered to separate the precipitate, removing tannins from the extract.
6. To the filtrate, hydrogen sulfide (H2S) gas is passed. If lead acetate is not initially added, the resulting precipitate will be lead sulfide (PbS), which is toxic and should be avoided. Therefore, it’s essential to ensure that no lead acetate is present during this step.
7. The extract is filtered again to separate any precipitates.
8. The filtrate obtained from the previous steps can be further purified through techniques such as fractional crystallization, distillation, or chromatography, which isolate the pure components of interest.
9. The molecular structure of the isolated glycoside can be determined through various analytical techniques, including spectrophotometry, ultraviolet-visible (UV-Vis) assays, infrared spectroscopy (IR), nuclear magnetic resonance spectroscopy (NMR), and mass spectrometry (MS), among others. This process allows for the isolation and characterization of glycosides from the original drug material, enabling their further study and application.
Applications of Glycosides
They have various applications and uses in different fields, including:
1. Medicinal Uses
Pharmaceuticals: Glycosides are used in the pharmaceutical industry to develop drugs and medicines. Some glycosides have therapeutic properties, such as cardiac glycosides like digoxin, which are used to treat heart conditions.
Herbal Medicine: Many traditional herbal remedies contain glycosides with medicinal properties. For example, salicin glycosides from willow bark were the basis for developing aspirin.
2. Flavor and Fragrance Industry
Natural Flavorings: Glycosides contribute to the flavors and aromas of various fruits and plants. For example, amygdalin in almonds and prunasin in cherries provide characteristic flavors.
Perfumery: Some glycosides found in flowers and aromatic plants are used as fragrance ingredients in perfumes and cosmetics.
3. Food Industry
Sweeteners: Certain glycosides, like stevioside from Stevia plants, are used as natural sweeteners and sugar substitutes.
Bitterness Masking: Some glycosides are used to mask bitterness in food and beverages, improving the taste of products.
4. Chemical Research
Analytical Chemistry: Glycosides are used as standards and markers in chemical analysis techniques, such as high-performance liquid chromatography (HPLC) and mass spectrometry, for identifying and quantifying compounds in complex mixtures.
Synthetic Chemistry: Glycosides are essential in the synthesis of more complex molecules, including antibiotics and anticancer drugs.
5. Plant Defense and Evolution
Plant Defense: Some glycosides play a role in plant defense mechanisms against herbivores and pathogens. For example, cyanogenic glycosides release toxic cyanide when broken down, deterring herbivores.
Plant Evolution: Glycosides have contributed to the evolution of plants by influencing interactions with pollinators, seed dispersers, and herbivores.
6. Microbiology
Microbial Glycosides: Certain microorganisms produce glycosides with antibacterial, antifungal, or antiviral properties, which can be explored for drug development.
7. Biotechnology
Enzymatic Processes: Glycosidases and glycosyltransferases are enzymes involved in glycoside metabolism. They are used in biotechnological applications, including glycoside synthesis and modification of bioactive compounds.
8. Insect Attractants and Pheromones
Some glycosides are used as attractants or pheromones in pest control strategies, such as trapping harmful insects or monitoring their populations.
9. Natural Products Chemistry
Glycosides are valuable natural products and are studied extensively in the field of natural product chemistry to discover new bioactive compounds.
10. Environmental Uses
In some cases, glycosides can be used as indicators of environmental pollutants or contaminants due to their presence or absence in specific plants or organisms in polluted areas.
These diverse applications and uses of glycosides highlight their significance in various scientific, industrial, and agricultural contexts.
Concepts Berg
What is the role of glycosides in plants?
In plants, glycosides often serve as storage forms of various bioactive compounds, including secondary metabolites and toxins.
How are glycosides formed in nature?
Glycosides can be formed enzymatically through glycosylation reactions, where a sugar molecule is attached to an aglycone.
Are glycosides found only in plants?
No, glycosides are found in various organisms, including plants, animals, and microorganisms.
How are glycosides commonly classified based on their aglycone component?
Glycosides are classified into several groups, including flavonoid glycosides, cardiac glycosides, and cyanogenic glycosides, based on their aglycone structures.
Can glycosides have biological activity?
Yes, many glycosides have biological activity due to the properties of their aglycone components. These activities can include antimicrobial, antioxidant, and anticancer effects, among others.
References Books
- A Textbook of Organic Chemistry book by Paula Yurkanis Bruice
References link
- An Article (chem.libretexts.org)
- An Article (wikipedia.org)
- An Article (chemistrysteps.com)
- An Article (solutionpharmacy.in)
