Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation

Ren Shi Shyu, Themmila Khamrang, Joen Rong Sheu, Chih Wei Hsia, Marappan Velusamy, Chih Hsuan Hsia, Duen Suey Chou, Chao Chien Chang

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Platelet activation has been reported to play a major role in arterial thrombosis, cancer metastasis, and progression. Recently, we developed a novel Ir(III)-based compound, [Ir(Cp)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]pyridine Cl]BF4 or Ir-6 and assessed its effectiveness as an antiplatelet drug. Ir-6 exhibited higher potency against human platelet aggregation stimulated by collagen. Ir-6 also inhibited ATP-release, intracellular Ca2+ mobilization, P-selectin expression, and the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), v-Akt murine thymoma viral oncogene (Akt)/protein kinase B, and mitogen-activated protein kinases (MAPKs), in collagen-activated platelets. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed the Ir-6-mediated inhibition of collagen-induced platelet aggregation. Moreover, Ir-6 did not considerably diminish OH radical signals in collagen-activated platelets or Fenton reaction solution. At 2 mg/kg, Ir-6 markedly prolonged the bleeding time in experimental mice. In conclusion, Ir-6 plays a crucial role by inhibiting platelet activation through the inhibition of signaling pathways, such as the PLCγ2-PKC cascade and the subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, Ir-6 is a potential therapeutic agent for preventing or treating thromboembolic disorders or disrupting the interplay between platelets and tumor cells, which contributes to tumor cell growth and progression.

Original languageEnglish
Article number8291393
Pages (from-to)8291393
JournalBioinorganic Chemistry and Applications
Volume2018
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Iridium
Platelet Activation
Organometallics
Platelets
Collagen
Chemical activation
Platelet Aggregation
Derivatives
Blood Platelets
Phospholipases
Mitogen-Activated Protein Kinases
Protein Kinase C
Viral Oncogene Proteins
Neoplasms
Proto-Oncogene Proteins c-akt
Bleeding Time
P-Selectin
Thymoma
Agglomeration
Guanylate Cyclase

ASJC Scopus subject areas

  • Biochemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Ir-6 : A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation. / Shyu, Ren Shi; Khamrang, Themmila; Sheu, Joen Rong; Hsia, Chih Wei; Velusamy, Marappan; Hsia, Chih Hsuan; Chou, Duen Suey; Chang, Chao Chien.

In: Bioinorganic Chemistry and Applications, Vol. 2018, 8291393, 01.01.2018, p. 8291393.

Research output: Contribution to journalArticle

Shyu, RS, Khamrang, T, Sheu, JR, Hsia, CW, Velusamy, M, Hsia, CH, Chou, DS & Chang, CC 2018, 'Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation', Bioinorganic Chemistry and Applications, vol. 2018, 8291393, pp. 8291393. https://doi.org/10.1155/2018/8291393
Shyu, Ren Shi ; Khamrang, Themmila ; Sheu, Joen Rong ; Hsia, Chih Wei ; Velusamy, Marappan ; Hsia, Chih Hsuan ; Chou, Duen Suey ; Chang, Chao Chien. / Ir-6 : A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation. In: Bioinorganic Chemistry and Applications. 2018 ; Vol. 2018. pp. 8291393.
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AB - Platelet activation has been reported to play a major role in arterial thrombosis, cancer metastasis, and progression. Recently, we developed a novel Ir(III)-based compound, [Ir(Cp)1-(2-pyridyl)-3-(4-dimethylaminophenyl)imidazo[1,5-a]pyridine Cl]BF4 or Ir-6 and assessed its effectiveness as an antiplatelet drug. Ir-6 exhibited higher potency against human platelet aggregation stimulated by collagen. Ir-6 also inhibited ATP-release, intracellular Ca2+ mobilization, P-selectin expression, and the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), v-Akt murine thymoma viral oncogene (Akt)/protein kinase B, and mitogen-activated protein kinases (MAPKs), in collagen-activated platelets. Neither the adenylate cyclase inhibitor SQ22536 nor the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one significantly reversed the Ir-6-mediated inhibition of collagen-induced platelet aggregation. Moreover, Ir-6 did not considerably diminish OH radical signals in collagen-activated platelets or Fenton reaction solution. At 2 mg/kg, Ir-6 markedly prolonged the bleeding time in experimental mice. In conclusion, Ir-6 plays a crucial role by inhibiting platelet activation through the inhibition of signaling pathways, such as the PLCγ2-PKC cascade and the subsequent suppression of Akt and MAPK activation, thereby ultimately inhibiting platelet aggregation. Therefore, Ir-6 is a potential therapeutic agent for preventing or treating thromboembolic disorders or disrupting the interplay between platelets and tumor cells, which contributes to tumor cell growth and progression.

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