title: Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists.
abstract: 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.
authors.affiliation: Department of Chemistry, Columbia University, 3000 Broadway, New York, New York 10027, USA.
authors.forename: Stine Byskov
authors.initials: SB
authors.lastname: Vogensen
authors.forename: Kristian
authors.initials: K
authors.lastname: Strømgaard
authors.forename: Hideo
authors.initials: H
authors.lastname: Shindou
authors.forename: Stanislav
authors.initials: S
authors.lastname: Jaracz
authors.forename: Makiko
authors.initials: M
authors.lastname: Suehiro
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ishii
authors.forename: Takao
authors.initials: T
authors.lastname: Shimizu
authors.forename: Koji
authors.initials: K
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D004224:Diterpenes; D046934:Ginkgolides; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011869:Radioligand Assay; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled; D013329:Structure-Activity Relationship
chemical_list: C471871:7-chloroginkgolide B; D004224:Diterpenes; D046934:Ginkgolides; D006576:Heterocyclic Compounds, 4 or More Rings; D007783:Lactones; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C039351:platelet activating factor receptor; C045856:ginkgolide B