Department of Pharmacology, Schools of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan.
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan.
Int J Mol Sci. 2018 Nov 19;19(11):3641. doi: 10.3390/ijms19113641.
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 ([Ca]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.
血小板在止血事件中起主要作用，并与各种病理事件相关，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品，因为它们在没有细胞毒性的情况下发挥有前途的抗癌作用。我们最近的研究发现，Ir 化合物具有很强的抗血小板特性。在这项研究中，我们评估了新合成的 Ir 配合物 Ir-1、Ir-2 和 Ir-4 的体外抗血小板、体内抗血栓形成和结构-活性关系（SAR），在激动剂诱导的人血小板中。在测试的化合物中，Ir-1 能有效抑制胶原诱导的血小板聚集；然而，Ir-2 和 Ir-4 即使在 50 μM 对胶原和 500 μM 对 U46619 诱导的聚集的最大浓度下也没有作用。同样，Ir-1 能有效抑制胶原诱导的三磷酸腺苷（ATP）释放、钙动员（[Ca]i）和 P-选择素表达，而无细胞毒性。同样，Ir-1 明显抑制胶原诱导的 Akt、PKC、p38MAPKs 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）诱导的小鼠闭合时间没有影响，但 Ir-1 在使用 C-ADP 刺激时导致显著增加。其他体内研究表明，Ir-1 显著延长血小板栓子形成时间，增加尾部出血时间，并降低小鼠腺苷二磷酸（ADP）诱导的急性肺血栓栓塞的死亡率。Ir-1 苯环上没有取代基，一个水分子（如顺铂）可以取代其氯离子，因此配体系统上的取代基可以调节水解速率。这些特征可能对观察到的 Ir-1 效应起作用。这些结果表明，Ir-1 可能是一种设计用于治疗血栓栓塞性疾病的新型抗血小板药物的先导化合物。
