Abstract
The edible grasshopper Oxya chinensis sinuosa is consumed worldwide for its various medicinal effects. The purpose of this study was to investigate potential bioactive antithrombotic and antiplatelet compounds from O. chinensis sinuosa. Five N-acetyldopamine dimers (1–5) were isolated from O. chinensis sinuosa and compounds 1 and 2 were identified as new chemicals with chiral centers at H-2 and H-3 of the benzo-1,4-dioxane structure. Compounds 1–4 were found to have both FXa and platelet aggregation inhibitory activities. These compounds inhibited the catalytic activity of FXa toward its synthetic substrate, S-2222, by noncompetitive inhibition, and inhibited platelet aggregation induced by ADP and U46619. Furthermore, compounds 1–4 showed enhanced antithrombotic effects, which were assessed using in vivo models of pulmonary embolism and arterial thrombosis. The isolated compounds also showed anticoagulant effects in mice. However, compounds 1–4 did not prolong bleeding time in mice, as shown by tail clipping. N-Acetyldopamine dimers, including two new stereoisomers 1 and 2, are novel antithrombotic compounds showing both FXa inhibition and antiplatelet aggregation activity with a low bleeding risk. Collectively, these results suggest that compounds 1–4 could serve as candidates and provide scaffolds for development of new antithrombotic drugs.
Highlights
Thrombosis plays a leading role in causing death and a major role in the onset of many cardiovascular diseases, such as acute coronary syndrome, myocardial infarction, and deep vein thrombosis[1]
The dose required to avoid thrombus formation and to protect against paralysis or death in mice was determined to be 5 μM per mouse (Fig. 7C). At double this concentration (i.e., 10 μM), bleeding time was not significantly longer in mice treated with compounds [1,2,3,4] than that of mice treated with vehicle (13.5 ± 1.3, 12.5 ± 1.2, and 12.1 ± 1.1 min for compounds [1, 2], and 3, respectively, mean ± standard deviations (SD), n = 10), suggesting that compounds [1,2,3,4] confer a low bleeding risk. Several anticoagulants such as fondaparinux, warfarin, low-molecular-weight heparins (LMWHs), and unfractionated heparin are effective in the prevention and treatment of thrombotic diseases, these drugs have undesirable effects[24, 25]
FXa became a promising target for the development of potent and selective anticoagulants, especially since FXa is situated at the beginning of the intrinsic and extrinsic coagulation pathways[6, 7]
Summary
Thrombosis plays a leading role in causing death and a major role in the onset of many cardiovascular diseases, such as acute coronary syndrome, myocardial infarction, and deep vein thrombosis[1]. In view of the bleeding risk, it may be safer to selectively inhibit blood clotting factors located upstream of thrombin In this regard, FXa has recently gained attention as a target of new antithrombotic agents[6, 7]. O. chinensis sinuosa, has long been used as food in Asia, there is little information on its chemical constituents or their activities, including antithrombotic and antiplatelet effects. During a screening for natural antithrombotic and antiplatelet products from insects, the ethyl acetate-soluble fraction derived from O. chinensis sinuosa showed potent inhibition of FXa generation in human umbilical vein endothelial cells (HUVECs). To the best of our knowledge, this is the first report regarding the antithrombotic and antiplatelet effects of O. chinensis sinuosa, and the discovery of new compounds demonstrating dual inhibition of FXa and platelet aggregation
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