Coumarin Derivatives Inhibit ADP-Induced Platelet Activation and Aggregation

Abstract

Coumarin was first discovered in Tonka bean and then widely in other plants. Coumarin has an anticoagulant effect, and its derivative, warfarin, is a vitamin K analogue that inhibits the synthesis of clotting factors and is more widely used in the clinical treatment of endovascular embolism. At present, many artificial chemical synthesis methods can be used to modify the structure of coumarin to develop many effective drugs with low toxicity. In this study, we investigated the effects of six coumarin derivatives on the platelet aggregation induced by adenosine diphosphate (ADP). We found that the six coumarin derivatives inhibited the active form of GPIIb/IIIa on platelets and hence inhibit platelet aggregation. We found that 7-hydroxy-3-phenyl 4H-chromen-4-one (7-hydroxyflavone) had the most severe effect. In addition, we further analyzed the downstream signal transduction of the ADP receptor, including the release of calcium ions and the regulation of cAMP, which were inhibited by the six coumarin derivatives selected in this study. These results suggest that coumarin derivatives inhibit coagulation by inhibiting the synthesis of coagulation factors and they may also inhibit platelet aggregation.

Unveiling the antitumor potential of novel N-(substituted-phenyl)-8-methoxycoumarin-3-carboxamides as dual inhibitors of VEGFR2 kinase and cytochrome P450 for targeted treatment of hepatocellular carcinoma

“…Coumarin-based compounds have gained increasing attention due to their broad range of biological activities (Ahmed et al, 2020;Küpeli Akkol et al, 2020;Wu et al, 2020;Rawat and Vijaya Bhaskar Reddy, 2022). They have been reported to exhibit anticoagulant (Lu et al, 2022), antibacterial (Liu H. et al, 2020;Qin et al, 2020;Hu Y. et al, 2021), anti-inflammatory (Liang et al, 2020;Nayeli et al, 2020;Wang et al, 2020;Alfayomy et al, 2021), antioxidant (Sanches et al, 2019;Li et al, 2020;Ozalp et al, 2020;Parvin et al, 2021), antitumor (Kaur et al, 2015;Mohammed et al, 2020;Shahzadi et al, 2020;Konkoľová et al, 2021;Zhang et al, 2021;Rawat and Vijaya Bhaskar Reddy, 2022), antiviral (Liu G.-L. et al, 2020;Chidambaram et al, 2021;Shan et al, 2021;Özdemir et al, 2022), hyperlipidemia (Miao et al, 2021), anti-Alzheimer (Francisco et al, 2020), and enzyme inhibition effects (Zengin Kurt et al, 2019;Supuran, 2020;Xu et al, 2020;Meleddu et al, 2021). In the context of cancer treatment, coumarin analogues have been gaining increasing attention in recent years due to their potential as anticancer agents against liver cancer (Küpeli Akkol et al, 2020;Wu et al, 2020;Rawat and Vijaya Bhaskar Reddy, 2022).…”

5,7- Dimethoxycoumarin Enhances Insulin Release and Stimulates Extrapancreatic Secretion of Amylin.

“…. 5,7-dimethoxycoumarin will nd special application in diabetics with chronic complications, against coagulopathy, platelet hyperactivity, thrombosis (14) (13), vasoconstriction, atherosclerosis (57), neuropathic pains and peripheral neuropathy (58), Amyloidosis (37) (38) (39) and effects of advanced glycation end products (59). 9.…”

“…Unlike the avonoids whose effects are predominantly antioxidant in nature, coumarins have direct anticoagulation pharmacological activities on the cardiovascular systems, not linked to antioxidant effects (13) by inhibiting the activation of Vitamin K and blocking the synthesis of coagulation factors. Coumarins also have direct antiplatelet effects by inhibiting ADP (13) (14) and vasodilating activities by inhibition of calcium in ux into the cell through calcium channel blockage (13) (15).…”

Electrochemical Anticoagulant Method

“…Warfarin is the only coumarin that is used in humans. Coumarin-like drugs bind to vitamin K epoxide reductase complex 1 in the liver and prevent the conversion of inactive oxidative vitamin K to active reducing vitamin K. Therefore, this compound is an anti-coagulant that limits access to vitamin K; this vitamin affects the blood coagulation pathway via coagulation factors II, VII, IX and X. Pindone and Diphenadione are indane diones with anti-coagulant effects in a similar way to coumarins and are mainly used for pest control, mouse, rat, and rabbit population control [14].…”