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

Abstract

Abstract 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 μM), 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 . Drug Dev. Res. 54:191–201, 2001. © 2002 Wiley‐Liss, Inc.