Structure-antiplatelet activity relationships of novel ruthenium (ii) complexes: Investigation of its molecular targets

Chih Hsuan Hsia, Thanasekaran Jayakumar, Joen Rong Sheu, Shin Yi Tsao, Marappan Velusamy, Chih Wei Hsia, Duen Suey Chou, Chao Chien Chang, Chi Li Chung, Themmila Khamrang, Kao Chang Lin

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Abstract

The regulation of platelet function by pharmacological agents that modulate platelet signaling has proven to be a positive approach to the prevention of thrombosis. Ruthenium complexes are fascinating for the development of new drugs, as they possess numerous chemical and biological properties. The present study aims to evaluate the structure-activity relationship (SAR) of newly synthesized ruthenium (II) complexes, TQ-1, TQ-2 and TQ-3 in agonists-induced washed human platelets. Silica gel column chromatography, aggregometry, immunoblotting, NMR, and X-ray analyses were performed in this study. Of the three tested compounds, TQ-3 showed a concentration (1–5 µM) dependent inhibitory effect on platelet aggregation induced by collagen (1 µg/mL) and thrombin (0.01 U/mL) in washed human platelets; however, TQ-1 and TQ-2 had no response even at 250 µM of collagen and thrombin-induced aggregation. TQ-3 was effective with inhibiting collagen-induced ATP release, calcium mobilization ([Ca2+]i) and P-selectin expression without cytotoxicity. Moreover, TQ-3 significantly abolished collagen-induced Lyn-Fyn-Syk, Akt-JNK and p38 mitogen-activated protein kinases (p38 MAPKs) phosphorylation. The compound TQ-3 containing an electron donating amino group with two phenyl groups of the quinoline core could be accounted for by its hydrophobicity and this nature might be the reason for the noted antiplatelet effects of TQ-3. The present results provide a molecular basis for the inhibition by TQ-3 in collagen-induced platelet aggregation, through the suppression of multiple machineries of the signaling pathway. These results may suggest that TQ-3 can be considered a potential agent for the treatment of vascular diseases.

Original languageEnglish
Article number477
JournalMolecules
Volume23
Issue number2
DOIs
Publication statusPublished - Feb 22 2018

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Keywords

  • Akt-JNK-p38
  • ATP
  • Lyn-Fyn-Syk
  • Platelets
  • Ruthenium complexes
  • SAR
  • [Ca]i
  • Ruthenium Compounds/chemical synthesis
  • Phosphorylation
  • Humans
  • Structure-Activity Relationship
  • Thrombosis/drug therapy
  • Platelet Activation/drug effects
  • Ruthenium/chemistry
  • Platelet Aggregation Inhibitors/chemical synthesis
  • Platelet Aggregation/drug effects
  • Collagen/chemistry
  • Blood Platelets/drug effects

ASJC Scopus subject areas

  • Organic Chemistry

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