Synthesis and biological studies of a new ginkgolide C derivative: Evidence that the cardioprotective effect of ginkgolides is unrelated to PAF inhibition

Ginkgolides have been demonstrated to protect the myocardium in experimental ischemia-reperfusion, but the extent to which this property is not related to platelet-activating factor (PAF) inhibition remains debated. This study was undertaken to determine whether a ginkgolide devoid of any anti-PAF activity could retain a cardioprotective activity. For this purpose, a new ginkgolide C (3) analogue, 7-O-(4-methylphenyl) ginkgolide C (4), was obtained from 3 with retention of configuration, using, in the key step, a copper-catalyzed arylation with tris-(4-methylphenyl) bismuth diacetate. No PAF inhibition on rabbit platelets in vitro was found for 4 up to 1.2.10(-4) M. However, 4 was found a significantly better preserving agent than 3 or ginkgolide B, a potent PAF inhibitor (all drugs at 0.35 muM), on hemodynamic and metabolic (i.e., myocardial ATP contents and enzymatic activities) indices measured in rat isolated hearts undergoing ischemia-reperfusion. The data provide additional support to a PAF-unrelated pharmacological activity for ginkgolides. Because the water solubility of 4, estimated by high-performance liquid chromatography analysis, was significantly lower than that of the parent molecule 3, a likely mechanism for the protective action of 4 involves its increased affinity for the myocardium, as compared to the relatively more hydrophilic 3. (C) 2002 Wiley-Liss, Inc.