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

2003; American Chemical Society; Volume: 46; Issue: 4 Linguagem: Inglês

10.1021/jm0203985

1520-4804

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

Neurological Disease Mechanisms and Treatments

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 7β-OH. Recently, we found that 7α-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 7β-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 7α-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 7α-substitutents had increased affinity compared to 7β-substituents, in particular 7α-chloro ginkgolide B, the most potent nonaromatic ginkgolide derivative described to date with a Ki value of 110 nM.