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

Sci Rep. 2017 Aug 25;7(1):9556. doi: 10.1038/s41598-017-09695-z.

Abstract

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(η6-cymene)2-(1H-benzoimidazol-2-yl)-quinoline Cl]BF4 (TQ-6), as a new antiplatelet drug. TQ-6 (0.3 µM) 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 Cγ2, protein kinase C, mitogen-activated protein kinases, and Akt. Neither FITC-JAQ1 nor FITC-triflavin binding or integrin β3 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-PLCγ2 cascade and subsequent suppression of granule secretion, leading to disturb integrin αIIbβ3-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers
  • Blood Coagulation / drug effects
  • Blood Coagulation Tests
  • Blood Platelets / drug effects
  • Blood Platelets / physiology
  • Cell Survival / drug effects
  • Humans
  • Male
  • Mice
  • Molecular Structure
  • Organometallic Compounds / chemistry*
  • Organometallic Compounds / pharmacology*
  • Phosphorylation
  • Platelet Activation / drug effects
  • Platelet Aggregation / drug effects
  • Platelet Aggregation Inhibitors / chemistry*
  • Platelet Aggregation Inhibitors / pharmacology*
  • Platelet Membrane Glycoproteins / metabolism
  • Ruthenium* / chemistry
  • Signal Transduction

Substances

  • Biomarkers
  • Organometallic Compounds
  • Platelet Aggregation Inhibitors
  • Platelet Membrane Glycoproteins
  • Ruthenium