Ginkgolides isolation

Nakanishi, K. Ginkgolides — isolation and structural studies carried out in the mid 1960 s. In Ginkgolides — Chemistry, Biology, Pharmacology. Barcelona, Spain J. R. Prous Science Pubbshers, 1988, 27-36. 

These compounds were first isolated in 1932 by Furukawa [176] from the bitter principles of Ginkgo biloba, but their structures have been resolved only recently. In 1967, Nakanishi s group reported their structures and called them Ginkgolides A, B, C and M (25a,b,c,e) [177-181], These are termed BN 52020, BN 52021, BN 52022 and BN 52023, respectively, in IHB nomenclature. A new ginkgolide, J (BN 52024 25d) has been recently identified [182]. All these compounds differ only by the number and the position of hydroxy groups, which may be present on C1 C3 or C7 of the spirononane framework. 

Amri H, Drieu K, Papadopoulos V. (1997). Ex vivo regulation of adrenal cortical cell steroid and protein synthesis, in response to adrenocorticotropic hormone stimulation, by the Ginkgo biloba extract EGb 761 and isolated ginkgolide B. Endocrinology. 138(12) 5415-26. 

Amri H, Ogwuegbu SO, Boujrad N, Drieu K, Papadopoulos V. (1996). In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated ginkgolides. Endocrinology. 137(12) 5707-18. 

Wada K, Sasaki K, Miura K, Yagi M, Kubota Y, Matsumoto T, Haga M. (1993). Isolation of bilobalide and ginkgolide A from Ginkgo biloba L. shorten the sleeping time induced in mice by anesthetics. Biol Pharm Bull. 16(2) 210-12. 

Overall, however, the immensity of temperate land corresponds to a most various secondary metabolic production, different from that of tropical land. The most renowned alkaloids belong to the morphine class (Chart 6.2.A1), and, in combination with isoprenoids, to the ergot and triterpene classes (Chart 6.2. A2). Prominent in the peptides are the cyclosporins (the first of which was isolated from a fiingus collected in Norway), streptogramins, and P-lactams (Chart 6.2.P). The isoprenoids are represented by pyrethrin monoterpenes, cedrane sesquiterpenes, ginkgolide and taxane diterpenes, ophiobolane sesterterpenes, and arborane and amyrin-like triterpenes (Chart 6.2.1). In the polyketides, epothilones, recently discovered from Myxobacteria, and the long known rapamycin, are two prominent classes of macrolides (Chart 6.2.FA/PO/C). 

Bilobalide (40) was isolated from the leaves by Wsinges ef al. [41], and is a sesquiterpene lactone, which has a Cert-butyl group and two hydroxyl groups in its chemical structure [42]. The ginkgo terpenes described above (bilobalide and ginkgolides) seem to be unique constituents to Ginkgo biloba because they have never been found in any other plants. 

Since the initial structural studies, a substantial effort has been made to simplify the isolation and quantification of ginkgolides, which was recently reviewed by van Beek. The first step is extraction from the leaves, which in most cases has been accomplished with various water-containing solvent systems, thereby excluding apolar constituents and collecting the ginkgolides. A more simplified extraction method was recently published, in which the dried leaves are boiled in dilute hydrogen peroxide and extracted with ethyl acetate to give an off-white powder with a... 

Recently, a key player in the ginkgolide biosynthesis has been isolated and characterized A cDNA that encodes G. biloba levopimaradiene synthase, a diterpene synthase involved in ginkgolide biosynthesis, was isolated and characterized. Similarly, a new geranylgeranyl diphosphate synthase gene from G. biloba, was characterized. ... 

Braquet, P. The ginkgolides potent platelet-activating factor antagonists isolated from Ginkgo biloba L. chemistry, pharmacology and clinical applications. Drugs Future, 1987, 12 643-699. 

Approximately 70% of ginkgolide A, 50% of ginkgolide B, and 30% of bilobalide is excreted unchanged in the urine (19). Metabolites isolated from human urine after administration of EGb include a 4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, hippuric acid, and 3-methoxy-4-hydroxybenzoic acid (vanillic acid) (53). In accord with previous data, these metabolites accounted for less than 30% of the administered EGb dose. Metabolites were not detectable in blood samples. 

A study (Amri et al., 1996) of GB extract 761 in rats demonstrated that high doses (10-100 mg/kg) of the extract, as well as isolated ginkgolides A and B at doses of 2 mg/kg, decreased corticosteroid synthesis by up to 50% and 60%, respectively. An associated increase in adrenocorticotropic hormone (ACTH) levels was also seen. 

Finally, it has been reported that a sesquiterpene compound, bilobalid A, isolated from the leaves of the Ginkgo tree, appears to have structural similarities with the unusual diterpenoid ginkgolides, in which one of the y-lactone rings (ring f) has been removed. 

Genipin diglycoside (155) isolated from the bark of Adina polycephala showed in vitro inhibitory rate of 44.8% against the release of p-glucuronidase in rat polymorphonuclear (PMN) leukocytes induced by platelet-activating factor (PAF) at a concentration of 10 M the positive control ginkgolide B showed an inhibition rate of 78.8% at the same concentration [160]. 

Ginkgolides (16) have been isolated from Ginkgo biloba in high yields (0.1-0.25 %) [29]. The biosynthetic route for their formation is reported in Scheme 102.10. Extracts of the plant have been used traditionally to improve... 

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