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.
| Original language | English |
|---|---|
| Journal | Journal of Medicinal Chemistry |
| Volume | 46 |
| Issue number | 4 |
| Pages (from-to) | 601-608 |
| Number of pages | 8 |
| ISSN | 0022-2623 |
| DOIs | |
| Publication status | Published - 13 Feb 2003 |
Keywords
- 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