Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists
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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.
|Journal||Journal of Medicinal Chemistry|
|Number of pages||8|
|Publication status||Published - 13 Feb 2003|
- 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