Preparation of 7-Substituted Ginkgolide Derivatives:  Potent Platelet Activating Factor (PAF) Receptor Antagonists

Vogensen, Stine B.; Strømgaard, Kristian; Shindou, Hideo; Jaracz, Stanislav; Suehiro, Makiko; Ishii, Satoshi; Shimizu, Takao; Nakanishi, Koji

doi:10.1021/jm0203985

Cited by 56 publications

(51 citation statements)

References 27 publications

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“…In general, 10-OH is the most reactive for alkylation and esterification. [35] However, acid-catalyzed esterification, [36] reaction of GC (3) with alkyl and aryl sulfonyl halides in the presence of pyridine [37,38] as well as silylation [39] takes place at 7-OH; a selective silylation at 1-OH in the presence of imidazole has also been described. [40] The use of solid-phase synthesis (SPS) for the preparation of ginkgolide derivatives appeared to be particularly attractive, as the presence of multiple hydroxyl groups provides several options for connecting points.…”

Section: Resultsmentioning

confidence: 99%

Ginkgolides and Glycine Receptors: A Structure–Activity Relationship Study

Jaracz

Nakanishi

Jensen

et al. 2004

Chemistry A European J

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Ginkgolides from the Ginkgo biloba tree are diterpenes with a cage structure consisting of six five-membered rings and a unique tBu group. They exert a variety of biological properties. In addition to being antagonists of the platelet activating factor receptor (PAFR), it has recently been shown that native ginkgolides are potent and selective antagonists of the inhibitory glycine receptor. Forty new ginkgolide derivatives have been prepared in good to high yields on milligram scales and investigated for their antagonistic properties at homomeric alpha 1 glycine receptors, thus providing the first structure-activity relationship study of ginkgolides at glycine receptors. A high-throughput screening assay showed that native ginkgolide C was the most potent ligand, and that manipulation of any of the hydroxyl groups led to loss of activity at alpha 1 glycine receptors.

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Section: Resultsmentioning

confidence: 99%

Ginkgolides and Glycine Receptors: A Structure–Activity Relationship Study

Jaracz

Nakanishi

Jensen

et al. 2004

Chemistry A European J

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“…Biological effects of ginkgolides can markedly vary with minor differences in their chemical structure. For example, the presence of one extra hydroxyl group at position 7 converts GB, a potent PAFR antagonist (K i ϭ 0.88 M) into GC, a constituent with much lower activity (K i ϭ 12.6 M) (Vogensen et al, 2003). Indeed, GA and GJ are the components of the extract that inhibit or even eliminate the deadly effects of A␤ on LTP (Nakanishi, 2005).…”

Section: Egb 761 and Ginkgolide A Inhibit A␤ Oligomerizationmentioning

confidence: 99%

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Wu¹,

Wu²,

Butko³

et al. 2006

J. Neurosci.

378

366

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Amyloid-␤ (A␤) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardized Ginkgo biloba extract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits A␤-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate A␤ species with A␤-induced pathological behaviors in a model organism, Caenorhabditis elegans. We report that EGb 761 and one of its components, ginkgolide A, alleviates A␤-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenic C. elegans. We also show that EGb 761 inhibits A␤ oligomerization and A␤ deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress A␤-induced paralysis because the antioxidant L-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenic C. elegans. These findings suggest that (1) EGb 761 suppresses A␤-related pathological behaviors, (2) the protection against A␤ toxicity by EGb 761 is mediated primarily by modulating A␤ oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

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“…As a result, they participate in the development of SAP and aggravate the injuries of pancreas and other organs or even cause SIRS, ARDS and MOF [4] . BN52021, one of the effective components of Chinese medicine ginkgo biloba leaf and a strong antagonist against the inflammatory medium of PAF, can not only block the signal transduction of PAF but also decrease blood concentration of PAF to exert its biological effect [17] . This study showed that BN52021 could decrease serum amylase level and alleviate pathological changes in SAP, which is consistent with that reported by other researchers [18,19] .…”

Section: Discussionmentioning

confidence: 99%

Effect of BN52021 on NFκ-Bp65 expression in pancreatic tissues of rats with severe acute pancreatitis

Xia

Fang²,

Hu³

et al. 2007

WJG

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AIM:To investigate dynamic changes and significance of expression of NF-κBp65 in pancreatic tissues of rats with severe acute pancreatitis (SAP), as well as BN52021 effects. METHODS:Wistar male rats were randomly divided into negative control group (NC group, n = 60), SAP-model group (SAP group, n = 60), and BN52021-treated group (BN group, n = 60), and each of the above groups was respectively divided into 6 subgroups at different time points after operation (1 h, 2 h, 3 h, 6 h, 12 h, and 24 h) (n = 10). By RT-PCR and Western blot, NF-κBp65 mRNA and its protein expression in pancreatic tissues of rats were detected respectively. R E S U LT S :T h e e x p r e s s i o n o f N F -κ B p 6 5 m R N A dynamically changed in both SAP groups and BN groups. The mRNA level was higher in SAP groups than NC groups at 2 h, 3 h, 12 h, and 24 h after operation (P < 0.05), higher in BN groups than NC groups at all time points (P < 0.05), and higher in BN groups than SAP group at 1 h (P < 0.05). The NF-κBp65 protein level was higher in SAP groups than NC groups at 1 h, 3 h, and 6 h (P < 0.01), and 2 h, 12 h, and 24 h (P < 0.05), higher in BN groups than NC groups at all time points (P < 0.05), and lower in BN groups than SAP groups at 1 h, 3 h, and 6 h (P < 0.05). CONCLUSION:T h e e x p r e s s i o n o f N F -κB p 6 5 i n pancreatic tissues is dynamically changed and the changes play an important role in pathogenesis of SAP.

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Preparation of 7-Substituted Ginkgolide Derivatives: Potent Platelet Activating Factor (PAF) Receptor Antagonists

Cited by 56 publications

References 27 publications

Ginkgolides and Glycine Receptors: A Structure–Activity Relationship Study

Ginkgolides and Glycine Receptors: A Structure–Activity Relationship Study

Amyloid-β-Induced Pathological Behaviors Are Suppressed byGinkgo bilobaExtract EGb 761 and Ginkgolides in TransgenicCaenorhabditis elegans

Effect of BN52021 on NFκ-Bp65 expression in pancreatic tissues of rats with severe acute pancreatitis

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