Glycoside

July 9, 2023
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In chemistry, a glycoside is a molecule in which a sugar is bound to another functional group via a glycosidic bond. Glycosides play numerous important roles in living organisms. Many plants store chemicals in the form of inactive glycosides. These can be activated by enzyme hydrolysis, which causes the sugar part to be broken off, making the chemical available for use. Many such plant glycosides are used as medications.

  • Brito-Arias, Marco (2007). Synthesis and Characterization of Glycosides. Springer. ISBN 978-0-387-26251-2.

Several species of Heliconius butterfly are capable of incorporating these plant compounds as a form of chemical defense against predators.

  • Nahrstedt, A.; Davis, R.H. (1983). “Occurrence, variation and biosynthesis of the cyanogenic glucosides linamarin and lotaustralin in species of the Heliconiini (Insecta: Lepidoptera)”. Comparative Biochemistry and Physiology Part B: Comparative Biochemistry. 75 (1): 65–73. doi:10.1016/0305-0491(83)90041-x.

In animals and humans, poisons are often bound to sugar molecules as part of their elimination from the body.

In formal terms, a glycoside is any molecule in which a sugar group is bonded through its anomeric carbon to another group via a glycosidic bond. Glycosides can be linked by an O- (an O-glycoside), N- (a glycosylamine), S-(a thioglycoside), or C- (a C-glycoside) glycosidic bond. According to the IUPAC, the name “C-glycoside” is a misnomer; the preferred term is “C-glycosyl compound”.

The given definition is the one used by IUPAC, which recommends the Haworth projection to correctly assign stereochemical configurations.

  •  Lindhorst, T.K. (2007). Essentials of Carbohydrate Chemistry and Biochemistry. Wiley-VCH. ISBN 978-3-527-31528-4.

Many authors require in addition that the sugar be bonded to a non-sugar for the molecule to qualify as a glycoside, thus excluding polysaccharides. The sugar group is then known as the glycone and the non-sugar group as the aglycone or genin part of the glycoside. The glycone can consist of a single sugar group (monosaccharide), two sugar groups (disaccharide), or several sugar groups (oligosaccharide).

The first glycoside ever identified was amygdalin, by the French chemists Pierre Robiquet and Antoine Boutron-Charlard, in 1830.

Related compounds

Molecules containing an N-glycosidic bond are known as glycosylamines. Many authors in biochemistry call these compounds N-glycosides and group them with the glycosides; this is considered a misnomer and is discouraged by the International Union of Pure and Applied Chemistry. Glycosylamines and glycosides are grouped together as glycoconjugates; other glycoconjugates include glycoproteins, glycopeptides, peptidoglycans, glycolipids, and lipopolysaccharides.[citation needed]

Chemistry

Much of the chemistry of glycosides is explained in the article on glycosidic bonds. For example, the glycone and aglycone portions can be chemically separated by hydrolysis in the presence of acid and can be hydrolyzed by alkali. There are also numerous enzymes that can form and break glycosidic bonds. The most important cleavage enzymes are the glycoside hydrolases, and the most important synthetic enzymes in nature are glycosyltransferases. Genetically altered enzymes termed glycosynthases have been developed that can form glycosidic bonds in excellent yield.[citation needed]

There are many ways to chemically synthesize glycosidic bonds. Fischer glycosidation refers to the synthesis of glycosides by the reaction of unprotected monosaccharides with alcohols (usually as solvent) in the presence of a strong acid catalyst.

Fischer glycosidation

Fischer glycosidation (or Fischer glycosylation) refers to the formation of a glycoside by the reaction of an aldose or ketose with an alcohol in the presence of an acid catalyst. The reaction is named after the German chemist, Emil Fischer, winner of the Nobel Prize in chemistry, 1902, who developed this method between 1893 and 1895.

Commonly, the reaction is performed using a solution or suspension of the carbohydrate in the alcohol as the solvent. The carbohydrate is usually completely unprotected. The Fischer glycosidation reaction is an equilibrium process and can lead to a mixture of ring size isomers, and anomers, plus in some cases, small amounts of acyclic forms. With hexoses, short reactions times usually lead to furanose ring forms, and longer reaction times lead to pyranose forms. With long reaction times the most thermodynamically stable product will result which, owing to the anomeric effect, is usually the alpha anomer.

See also

The Koenigs-Knorr reaction is the condensation of glycosyl halides and alcohols in the presence of metal salts such as silver carbonate or mercuric oxide.[citation needed]

Koenigs-Knorr reaction

The Koenigs–Knorr reaction in organic chemistry is the substitution reaction of a glycosyl halide with an alcohol to give a glycoside. It is one of the oldest glycosylation reactions. It is named after Wilhelm Koenigs (1851–1906), a student of von Baeyer and fellow student with Hermann Emil Fischer, and Edward Knorr, a student of Koenigs.

In its original form, Koenigs and Knorr treated acetobromoglucose with alcohols in the presence of silver carbonate. Shortly afterwards Fischer and Armstrong reported very similar findings.

In the above example, the stereochemical outcome is determined by the presence of the neighboring group at C2 that lends anchimeric assistance, resulting in the formation of a 1,2-trans stereochemical arrangement. Esters (e.g. acetyl, benzoyl, pivalyl) generally provide good anchimeric assistance, whereas ethers (e.g. benzyl, methyl etc.) do not, leading to mixtures of stereoisomers.

Mechanism

In the first step of the mechanism, the glycosyl bromide reacts with silver carbonate upon elimination of silver bromide and the silver carbonate anion to the oxocarbenium ion. From this structure a dioxolanium ring is formed, which is attacked by methanol via an SN
2 mechanism at the carbonyl carbon atom. This attack leads to the inversion. After deprotonation of the intermediate oxonium, the product glycoside is formed.

  • Kürti, László; Czakó, Barbara (2005). Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms. Elsevier. p. 246–7. ISBN 978-0-12-429785-2.

The reaction can also be applied to carbohydrates with other protecting groups. In the oligosaccharide synthesis in place of the methanol other carbohydrates are used, which have been modified with protective groups in such a way that only one hydroxyl group is accessible.

History

The method was later transferred by Emil Fischer and Burckhardt Helferich to other chloro-substituted purines and produced thus for the first time synthetic nucleosides. It was later improved and modified by numerous chemists.

Alternative reactions

Generally, the Koenigs–Knorr reaction refers to the use of glycosyl chlorides, bromides and more recently iodides as glycosyl donors. The Koenigs–Knorr reaction can be performed with alternative promoters such as various heavy metal salts including mercuric bromide/mercuric oxide, mercuric cyanide and silver triflate.

When mercury salts are used, the reaction is normally called the Helferich method. Other glycosidation methods are Fischer glycosidation, use of glycosyl acetates, thioglycosides, glycosyl trichloroacetimidates, glycosyl fluorides or n-pentenyl glycosides as glycosyl donors, or intramolecular aglycon delivery.

Classification (of glycosides)

Glycosides can be classified by the glycone, by the type of glycosidic bond, and by the aglycone.

By glycone/presence of sugar

If the glycone group of a glycoside is glucose, then the molecule is a glucoside; if it is fructose, then the molecule is a fructoside; if it is glucuronic acid, then the molecule is a glucuronide; etc. In the body, toxic substances are often bonded to glucuronic acid to increase their water solubility; the resulting glucuronides are then excreted. Compounds can also be generally defined based on the class of glycone; for example, biosides are glycosides with a disaccharide (biose) glycone.

By type of glycosidic bond

Depending on whether the glycosidic bond lies “below” or “above” the plane of the cyclic sugar molecule, glycosides are classified as α-glycosides or β-glycosides. Some enzymes such as α-amylase can only hydrolyze α-linkages; others, such as emulsin, can only affect β-linkages.

There are four type of linkages present between glycone and aglycone:

  • C-linkage/glycosidic bond, “nonhydrolysable by acids or enzymes”
  • O-linkage/glycosidic bond
  • N-linkage/glycosidic bond
  • S-linkage/glycosidic bond

By aglycone

Glycosides are also classified according to the chemical nature of the aglycone. For purposes of biochemistry and pharmacology, this is the most useful classification.

Alcoholic glycosides

An example of an alcoholic glycoside is salicin, which is found in the genus Salix. Salicin is converted in the body into salicylic acid, which is closely related to aspirin and has analgesic, antipyretic, and anti-inflammatory effects.

Anthraquinone glycosides

These glycosides contain an aglycone group that is a derivative of anthraquinone. They have a laxative effect. They are mainly found in dicot plants except the family Liliaceae which are monocots. They are present in senna, rhubarb and Aloe species. Anthron and anthranol are reduced forms of anthraquinone.

Coumarin glycosides

Here, the aglycone is coumarin or a derivative. An example is apterin which is reported to dilate the coronary arteries as well as block calcium channels. Other coumarin glycosides are obtained from dried leaves of Psoralea corylifolia.

Chromone glycosides

In this case, the aglycone is called benzo-gamma-pyrone.

Cyanogenic glycosides

In this case, the aglycone contains a cyanohydrin group. Plants that make cyanogenic glycosides store them in the vacuole, but, if the plant is attacked, they are released and become activated by enzymes in the cytoplasm. These remove the sugar part of the molecule, allowing the cyanohydrin structure to collapse and release toxic hydrogen cyanide. Storing them in inactive forms in the vacuole prevents them from damaging the plant under normal conditions.

Along with playing a role in deterring herbivores, in some plants they control germination, bud formation, carbon and nitrogen transport, and possibly act as antioxidants. The production of cyanogenic glycosides is an evolutionarily conserved function, appearing in species as old as ferns and as recent as angiosperms. These compounds are made by around 3,000 species. In screens they are found in about 11% of cultivated plants but only 5% of plants overall; humans seem to have selected for them.

Examples include amygdalin and prunasin which are made by the bitter almond tree; other species that produce cyanogenic glycosides are sorghum (from which dhurrin, the first cyanogenic glycoside to be identified, was first isolated), barley, flax, white clover, and cassava, which produces linamarin and lotaustralin.

Amygdalin and a synthetic derivative, laetrile, were investigated as potential drugs to treat cancer and were heavily promoted as alternative medicine; they are ineffective and dangerous.

Some butterfly species, such as the Dryas iulia and Parnassius smintheus, have evolved to use the cyanogenic glycosides found in their host plants as a form of protection against predators through their unpalatability.

Flavonoid glycosides

Here, the aglycone is a flavonoid. Examples of this large group of glycosides include:

Among the important effects of flavonoids are their antioxidant effect. They are also known to decrease capillary fragility.

Phenolic glycosides

Here, the aglycone is a simple phenolic structure. An example is arbutin found in the Common Bearberry Arctostaphylos uva-ursi. It has a urinary antiseptic effect.

Saponins

Main article: Saponin

These compounds give a permanent froth when shaken with water. They also cause hemolysis of red blood cells. Saponin glycosides are found in liquorice. Their medicinal value is due to their expectorant, corticoid and anti-inflammatory effects. Steroid saponins are important starting material for the production of semi-synthetic glucocorticoids and other steroid hormones such as progesterone; for example in Dioscorea wild yam the sapogenin diosgenin, in the form of its glycoside dioscin. The ginsenosides are triterpene glycosides and ginseng saponins from Panax ginseng (Chinese ginseng) and Panax quinquefolius (American ginseng). In general, the use of the term saponin in organic chemistry is discouraged, because many plant constituents can produce foam, and many triterpene-glycosides are amphipolar under certain conditions, acting as a surfactant. More modern uses of saponins in biotechnology are as adjuvants in vaccines: Quil A and its derivative QS-21, isolated from the bark of Quillaja saponaria Molina, to stimulate both the Th1 immune response and the production of cytotoxic T-lymphocytes (CTLs) against exogenous antigens make them ideal for use in subunit vaccines and vaccines directed against intracellular pathogens as well as for therapeutic cancer vaccines but with the aforementioned side-effect of hemolysis. Saponins are also natural ruminal antiprotozoal agents that are potential to improve ruminal microbial fermentation reducing ammonia concentrations and methane production in ruminant animals.

Steroid glycosides (cardiac glycosides)

Main article: Cardiac glycoside

In these glycosides, the aglycone part is a steroid nucleus. These glycosides are found in the plant genera Digitalis, Scilla, and Strophanthus. They are used in the treatment of heart diseases, e.g., congestive heart failure (historically as now recognised does not improve survivability; other agents[example needed] are now preferred[medical citation needed]) and arrhythmia.

Steviol glycosides

Main article: Steviol glycoside

These sweet glycosides found in the stevia plant Stevia rebaudiana Bertoni have 40–300 times the sweetness of sucrose. The two primary glycosides, stevioside and rebaudioside A, are used as natural sweeteners in many countries. These glycosides have steviol as the aglycone part. Glucose or rhamnose-glucose combinations are bound to the ends of the aglycone to form the different compounds.

Iridoid glycosides

These contain an iridoid group; e.g. aucubin, geniposidic acid, theviridoside, loganin, catalpol.

Thioglycosides

As the name implies (q.v. thio-), these compounds contain sulfur. Examples include sinigrin, found in black mustard, and sinalbin, found in white mustard.

See also

References

  1. ^ Brito-Arias, Marco (2007). Synthesis and Characterization of Glycosides. Springer. ISBN 978-0-387-26251-2.
  2. ^ Nahrstedt, A.; Davis, R.H. (1983). “Occurrence, variation and biosynthesis of the cyanogenic glucosides linamarin and lotaustralin in species of the Heliconiini (Insecta: Lepidoptera)”. Comparative Biochemistry and Physiology Part B: Comparative Biochemistry. 75 (1): 65–73. doi:10.1016/0305-0491(83)90041-x.
  3. ^ “Glycosides”. IUPAC Gold Book – Glycosides. 2009. doi:10.1351/goldbook.G02661. ISBN 978-0-9678550-9-7.
  4. ^ Lindhorst, T.K. (2007). Essentials of Carbohydrate Chemistry and Biochemistry. Wiley-VCH. ISBN 978-3-527-31528-4.
  5. ^ Robiquet; Boutron-Charlard (1830). “Nouvelles expériences sur les amandes amères et sur l’huile volatile qu’elles fournissent” [New experiments on bitter almonds and the volatile oil that they provide]. Annales de Chimie et de Physique. 2nd series (in French). 44: 352–382.
  6. Gleadow, RM; Møller, BL (2014). “Cyanogenic glycosides: synthesis, physiology, and phenotypic plasticity”. Annual Review of Plant Biology. 65: 155–85. doi:10.1146/annurev-arplant-050213-040027. PMID 24579992.
  7. Milazzo, S; Horneber, M (28 April 2015). “Laetrile treatment for cancer”. The Cochrane Database of Systematic Reviews (4): CD005476. doi:10.1002/14651858.CD005476.pub4. PMC 6513327. PMID 25918920.
  8. Benson, Woodruff W. (1971). “Evidence for the Evolution of Unpalatability Through Kin Selection in the Heliconinae (Lepidoptera)”. The American Naturalist. 105 (943): 213–226. doi:10.1086/282719. JSTOR 2459551. S2CID 84261089.
  9. Doyle, Amanda (2011). The roles of temperature and host plant interactions in larval development and population ecology of Parnassius smintheus Doubleday, the Rocky Mountain Apollo butterfly (PDF) (MSc). University of Alberta. doi:10.7939/R3VX32. Retrieved 13 November 2017.
  10. Sun, Hong-Xiang; Xie, Yong; Ye, Yi-Ping (2009). “Advances in saponin-based adjuvants”. Vaccine. 27 (12): 1787–1796. doi:10.1016/j.vaccine.2009.01.091. PMID 19208455.
  11. Patra, AK; Saxena, J (2009). “The effect and mode of action of saponins on the microbial populations and fermentation in the rumen and ruminant production”. Nutrition Research Reviews. 22 (2): 204–209. doi:10.1017/S0954422409990163. PMID 20003589.

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