A novel ruthenium (II)- derived organometallic compound, TQ-6, potently inhibits platelet aggregation: Ex vivo and in vivo studies

作者：Hsia Chih Hsuan; Velusamy Marappan; Sheu Joen Rong; Khamrang Themmila; Jayakumar Thanasekaran; Lu Wan Jung; Lin Kuan Hung; Chang Chao Chien^*

来源：Scientific Reports, 2017, 7(1): 9556.

DOI：10.1038/s41598-017-09695-z

Arterial thrombosis plays a key role in cardiovascular diseases. Hence, developing more effective antithrombotic agents is necessary. We designed a ruthenium (II)-derived complex, [Ru(eta(6)-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl] BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 mu M) exhibited extremely strong inhibitory activity against platelet aggregation, Src, and Syk phosphorylation stimulated by agonists in human platelets. In collagen-activated platelets, TQ-6 also inhibited ATP-release, [Ca+2] i, P-selectin expression, FITC-PAC-1 binding, and hydroxyl radical formation, as well as the phosphorylation of phospholipase C gamma 2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin beta(3) phosphorylation stimulated by immobilized fibrinogen were diminished by TQ-6. Furthermore, TQ-6 had no effects in cyclic nucleotide formation. Moreover, TQ-6 substantially prolonged the closure time in whole blood, increased the occlusion time of thrombotic platelet plug formation and bleeding time in mice. In conclusion, TQ-6 has a novel role in inhibiting platelet activation through the inhibition of the agonist receptors-mediated inside-out signaling such as Src-Syk-PLC gamma 2 cascade and subsequent suppression of granule secretion, leading to disturb integrin alpha(IIb)beta(3)-mediated outside-in signaling, and ultimately inhibiting platelet aggregation. Therefore, TQ-6 has potential to develop as a therapeutic agent for preventing or treating thromboembolic disorders.

• 出版日期2017-8-25
• 单位河北医科大学