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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Structure–Activity Relationship Study of Newly Synthesized Iridium-III Complexes as Potential Series for Treating Thrombotic Diseases
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Structure–Activity Relationship Study of Newly Synthesized Iridium-III Complexes as Potential Series for Treating Thrombotic Diseases

机译：新合成铱-Ⅲ配合物作为血栓性疾病治疗潜力系列的构效关系研究

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Platelets play a major role in hemostatic events and are associated with various pathological events, such as arterial thrombosis and atherosclerosis. Iridium (Ir) compounds are potential alternatives to platinum compounds, since they exert promising anticancer effects without cellular toxicity. Our recent studies found that Ir compounds show potent antiplatelet properties. In this study, we evaluated the in vitro antiplatelet, in vivo antithrombotic and structure–activity relationship (SAR) of newly synthesized Ir complexes, Ir-1, Ir-2 and Ir-4, in agonists-induced human platelets. Among the tested compounds, Ir-1 was active in inhibiting platelet aggregation induced by collagen; however, Ir-2 and Ir-4 had no effects even at their maximum concentrations of 50 μM against collagen and 500 μM against U46619-induced aggregation. Similarly, Ir-1 was potently inhibiting of adenosine triphosphate (ATP) release, calcium mobilization ([Ca2+]i) and P-selectin expression induced by collagen-induced without cytotoxicity. Likewise, Ir-1 expressively suppressed collagen-induced Akt, PKC, p38MAPKs and JNK phosphorylation. Interestingly, Ir-2 and Ir-4 had no effect on platelet function analyzer (PFA-100) collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) induced closure times in mice, but Ir-1 caused a significant increase when using C-ADP stimulation. Other in vivo studies revealed that Ir-1 significantly prolonged the platelet plug formation, increased tail bleeding times and reduced the mortality of adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism in mice. Ir-1 has no substitution on its phenyl group, a water molecule (like cisplatin) can replace its chloride ion and, hence, the rate of hydrolysis might be tuned by the substituent on the ligand system. These features might have played a role for the observed effects of Ir-1. These results indicate that Ir-1 may be a lead compound to design new antiplatelet drugs for the treatment of thromboembolic diseases.
机译：血小板在止血事件中起主要作用，并与各种病理事件有关，例如动脉血栓形成和动脉粥样硬化。铱（Ir）化合物是铂化合物的潜在替代物，因为它们发挥了有希望的抗癌作用而没有细胞毒性。我们最近的研究发现Ir化合物具有有效的抗血小板特性。在这项研究中，我们评估了激动剂诱导的人血小板中新合成的Ir配合物Ir-1，Ir-2和Ir-4的体外抗血小板，体内抗血栓形成和构效关系（SAR）。在被测化合物中，Ir-1具有抑制胶原蛋白诱导的血小板凝集的活性。然而，即使最大浓度为50μM（针对胶原蛋白）和500μM（针对U46619诱导的聚集），Ir-2和Ir-4也不起作用。同样，Ir-1可有效抑制胶原诱导的三磷酸腺苷（ATP）的释放，钙动员（[Ca 2 + ] i）和P-选择素的表达，而无细胞毒性。同样，Ir-1表达抑制胶原诱导的Akt，PKC，p38MAPK和JNK磷酸化。有趣的是，Ir-2和Ir-4对血小板功能分析仪（PFA-100）胶原-二磷酸腺苷（C-ADP）和胶原-肾上腺素（C-EPI）诱导的小鼠关闭时间无影响，但Ir-1引起使用C-ADP刺激时显着增加。其他体内研究表明，Ir-1显着延长了血小板栓塞的形成，增加了尾部出血时间并降低了二磷酸腺苷（ADP）诱导的小鼠急性肺血栓栓塞的死亡率。 Ir-1的苯基上没有取代基，水分子（如顺铂）可以取代其氯离子，因此，水解速度可能受配体系统上的取代基调节。这些功能可能对Ir-1的观察到的作用起作用。这些结果表明，Ir-1可能是设计用于治疗血栓栓塞性疾病的新抗血小板药物的先导化合物。

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