Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists

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

Ginkgolides are structurally unique constituents of Ginkgo biloba extracts and are known antagonists of the platelet-activating factor (PAF) receptor. Ginkgolide C is 25-fold less potent than ginkgolide B as a PAF receptor antagonist, due to the presence of the 7beta-OH. Recently, we found that 7alpha-fluoro ginkgolide B was equipotent to ginkgolide B underlining the critical importance of the 7-position of ginkgolides for PAF receptor activity. Herein we describe the synthesis of a series of ginkgolide B derivatives with modifications at the 7-position and the pharmacological evaluation of these derivatives as assayed by cloned PAF receptors. In two cases nucleophilic attack on a 7beta-O-triflate ginkgolide B did not lead to the expected products, but gave rise to two unprecedented ginkgolide derivatives, one with a novel rearranged skeleton. Furthermore, standard reduction of 7alpha-azido ginkgolide B did not give the expected primary amine, but instead yielded alkylated amines depending on the solvent employed. Pharmacological testing with cloned PAF receptors showed that ginkgolides with 7alpha-substitutents had increased affinity compared to 7beta-substituents, in particular 7alpha-chloro ginkgolide B, the most potent nonaromatic ginkgolide derivative described to date with a K(i) value of 110 nM.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume46
Issue number4
Pages (from-to)601-608
Number of pages8
ISSN0022-2623
DOIs
Publication statusPublished - 13 Feb 2003

    Research areas

  • Animals, Binding, Competitive, Diterpenes, Ginkgolides, Heterocyclic Compounds with 4 or More Rings, Lactones, Mice, Mice, Transgenic, Muscle, Skeletal, Myocardium, Platelet Activating Factor, Platelet Membrane Glycoproteins, Radioligand Assay, Receptors, Cell Surface, Receptors, G-Protein-Coupled, Structure-Activity Relationship

ID: 45810225