Ginkgolides are biologically active terpenic

lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...

s present in ''

Ginkgo biloba ''Ginkgo biloba'', commonly known as ginkgo or gingko ( ), also known as the maidenhair tree, is a species of gymnosperm tree native to East Asia. It is the last living species in the order Ginkgoales, which first appeared over 290 million year ...

''. They are

diterpenoid Diterpenes are a class of terpenes composed of four isoprene units, often with the molecular formula C20H32. They are biosynthesized by plants, animals and fungi via the HMG-CoA reductase pathway, with geranylgeranyl pyrophosphate being a primar ...

s with 20-carbon skeletons, which are biosynthesized from

geranylgeranyl pyrophosphate Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and diterpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls. It is also a precursor to geranylgeranylated proteins, whic ...

Examples

Ginkgolide B

Ginkgolide B, specifically, is a diterpenoid trilactone with six five-membered rings. It contains a spiro ,4nonane carbocyclic ring, a

tetrahydrofuran Tetrahydrofuran (THF), or oxolane, is an organic compound with the formula (CH2)4O. The compound is classified as heterocyclic compound, specifically a cyclic ether. It is a colorless, water- miscible organic liquid with low viscosity. It is ...

ring, and a very specific

tert-butyl In organic chemistry, butyl is a four-carbon alkyl radical or substituent group with general chemical formula , derived from either of the two isomers (''n''-butane and isobutane) of butane. The isomer ''n''-butane can connect in two ways, giv ...

group at one of the rings (Figure 1). The class of ginkgolides was first isolated from the tree ''

'' in 1932. Structural elucidation was accomplished in 1967 by Maruyama ''et al''.

Background

It is extracted from the root bark and leaves of the ''

'' (' meaning "silver apricot") tree found native in China. It is marketed to other countries that include Korea, France, the United States, etc. for the drug and clinical properties of the extracts. Present in the tree is less than 0.1 to 0.25% of ginkgolide B, the most abundant being ginkgolide A.

Potential applications

This class of molecules has been studied for its potential to act as a platelet-activating factor receptor

antagonist An antagonist is a character in a story who is presented as the main enemy or rival of the protagonist and is often depicted as a villain. Ginkgolide B has been investigated for its potential to reducing migraine frequency. Ginkgolide B is also used in treatment for

cerebrovascular disease Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. Th ...

. Research has also proven that ginkgolide B can also treat migraines in young ages. The literature indicates that ginkgolide B functions as a selective antagonist of glycine receptors based on noncompetitive inhibition for the neurological system that this compound performs.

Spectroscopic studies for the elucidation of the individual structures for the ginkgolides

Ginkolides A - C were isolated from a large scale

methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...

ic extraction followed by liquid-liquid partitions, column chromatography and repeated crystallizations. The molecular formulas were determined by high resolution mass spectrometry, and the overall structures by IR and NMR spectroscopic analysis and extensive derivitization techniques.

Biosynthesis of ginkgolide B

While researchers have published chemical pathways to make this molecule, most of the designed syntheses were too complex and produced little of the actual material to run full analyses. Therefore, studying the biosynthesis of the molecule is preferable. Most of the natural product terpenoids start with

isopentenyl diphosphate Isopentenyl pyrophosphate (IPP, isopentenyl diphosphate, or IDP) is an isoprenoid precursor. IPP is an intermediate in the classical, HMG-CoA reductase pathway (commonly called the mevalonate pathway) and in the ''non-mevalonate'' MEP pathway of i ...

synthesized by the

MEP pathway The non-mevalonate pathway—also appearing as the mevalonate-independent pathway and the 2-''C''-methyl-D-erythritol 4-phosphate/1-deoxy-D-xylulose 5-phosphate (MEP/DOXP) pathway—is an alternative metabolic pathway for the biosynthesis of the iso ...

. This pathway also generates

dimethylallyl diphosphate Dimethylallyl pyrophosphate (DMAPP; or alternatively, dimethylallyl diphosphate (DMADP); also isoprenyl pyrophosphate) is an isoprenoid precursor. It is a product of both the mevalonate pathway and the MEP pathway of isoprenoid precursor biosyn ...

, from

pyruvate Pyruvic acid (CH3COCOOH) is the simplest of the alpha-keto acids, with a carboxylic acid and a ketone functional group. Pyruvate, the conjugate base, CH3COCOO−, is an intermediate in several metabolic pathways throughout the cell. Pyruvic ...

and D-glyercaldehyde 3-phosphate (GAP). When coupled together, they form one molecule of

geranylgeranyl diphosphate Geranylgeranyl pyrophosphate is an intermediate in the biosynthesis of diterpenes and diterpenoids. It is also the precursor to carotenoids, gibberellins, tocopherols, and chlorophylls. It is also a precursor to geranylgeranylated proteins, whic ...

with geranylgeranyl diphosphate synthase. A molecule of GGPP generates (1) (+)-copalyl in the presence of

levopimaradiene synthase Levopimaradiene synthase (EC 4.2.3.32, ''PtTPS-LAS'', ''LPS'', copalyl-diphosphate diphosphate-lyase bieta-8(14),12-diene-forming'') is an enzyme with systematic name (+)-copalyl-diphosphate diphosphate-lyase (abieta-8(14),12-diene-forming). This ...

. (a) Then (1) loses its OPP group catalyzed by this same synthase, performing an intramolecular allylic cyclization with the two

alkenes In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...

, to form (2) the sandaracopimarenyl cation. (b) This cation then undergoes an internal cyclization to stabilize the

carbocation Carbocation is a general term for ions with a positively charged carbon atom. In the present-day definition given by the IUPAC, a carbocation is any even-electron cation with significant partial positive charge on a carbon atom. They are further ...

in the ring by proton transfer to form (3) intermediate. (c) By doing this, the molecule sets itself up for a methyl migration to stabilize that secondary cation and generate that tertiary

at (4). (d) This induces a loss of proton to get (5) levopimaradiene. (e) With oxidation, a loss of a proton to form an aromatic ring generates (6) abietatriene. (g) This newly formed abietatriene undergoes a 1,2-alkyl shift to break the 6-membered ring into (7) with a five-membered ring (more favorable). (h) Another 1,2-alkyl shift takes place at the same time a ring cleavage takes place to generate (8). (i) Oxidation at all the positions with

generates (9) intermediate which then undergoes ring closures featuring one

hemiacetal In organic chemistry, a hemiacetal is a functional group the general formula , where is a hydrogen atom or an organic substituent. They generally result from the nucleophilic Addition reaction, addition of an Alcohol (chemistry), alcohol (a compo ...

and all three

lactones Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corre ...

to get ginkgolide B at (10).

References

{{PAF signaling Gamma-lactones Diterpenes Glycine receptor antagonists Tert-butyl compounds Cyclopentanes