Amide Derivatives of Ginkgolide B and Their Inhibitory Effects on PAF-Induced Platelet Aggregation

Abstract

Ginkgolides are the most important components of Ginkgo biloba extracts, whose lactone can be hydrolyzed in the aqueous environment. Although the hydrolyzed products have complex structures and their functions are not well-understood, opening the lactone ring is an important strategy in producing novel derivatives of ginkgolide. The preparation of a single pure aminolyzed ginkgolide for the study of its bioactivity and understanding of the process of aminolysis are challenging. To obtain stable aminolyzed products, four amide derivatives (2–5) of ginkgolide B (GB, 1) were prepared via the ring-opening reaction of its lactone with propylamine. These products were purified and fully identified by high-resolution mass spectrometry (HRMS) and nuclear magnetic resonance (NMR) spectroscopy and were further evaluated for their ability to inhibit the PAF-induced platelet aggregation of rabbit platelets in vitro. Compound 2, which was obtained by selective aminolysis of the lactone ring C of GB, showed a much better inhibitory activity of platelet aggregation (IC50, 15 nM) than the parent compound GB (IC50, 442 nM). The other three products (3–5), which were obtained by the aminolysis of lactone rings C and F of GB, did not show platelet aggregation inhibitory activity. The results greatly extended our understanding of the chemistry of GB and provided important structural information for the exploration and development of new drugs based on ginkgolides in G. biloba.

Factors Influencing Venous Remodeling in the Development of Varicose Veins of the Lower Limbs

“…Gb also performs an important role in peripheral circulation and microcirculation. Ginkgolide B (GB) is the most potent antagonist of platelet-activating factor (PAF) and an intracellular mediator involved in the process of platelet aggregation and inflammatory reactions [204]. Ginkgolide A and B have antioxidant properties, inhibit the formation of ROS and induce an increase in SOD activity [205,206].…”

Anti-atherosclerotic effects and molecular targets of ginkgolide B from Ginkgo biloba

“…As the major integrin in platelets, α IIb β 3 is referred to as the glycoprotein GPIIb/IIIa (CD41/CD61) complex, which can bind to vWF, fibrinogen, and other ligands 108 , showing that platelet activation is a multifactorial process. Notwithstanding the strong inhibitory effects of GB on platelet adhesion 33 , 39 , 109 , its mechanism of action is unclear. Since GBE preparations can reduce the level of vWF in plasma 110 , 111 , it can be speculated that GB might inhibit platelet adhesion by reducing the binding of vWF to α IIb β 3 .…”

Therapeutic Applications of Ginkgo biloba L. Tree: Systemic Review

“…PAF, an inflammatory mediator capable of generating persistent inflammation of the airways and bronchial hyperreactivity, has been demonstrated to be inhibited by Ginkgolide B in G. biloba. [42][43][44][45][46] GB believed to have a contribution in the treatment of bronchial asthma by decreasing the activation of asthmatic patients' human peripheral blood mononuclear cells. 42,47 Protein kinase C (PKC) activation is required for PAF activation on asthma, and GB, a natural PAF antagonist, can prevent PAF-mediated inflammatory reactions.…”