Novel iridium (III)‑derived organometallic compound for the inhibition of human platelet activation.

Abstract

Since cisplatin achieved clinical success, transition metal platinum (Pt) drugs have been effectively used for the treatment of cancer. Iridium (Ir) compounds are considered to be potential alternatives to Pt compounds, as they possess promising anticancer effects with minor side effects. Platelet activation is associated with the metastasis and progression of cancer, and also with arterial thrombosis. Therefore, it is necessary to develop novel, effective antithrombotic agents. An Ir (III)-derived complex, [Ir (Cp*) 1-(2-pyridyl)-3-(3-me-thoxyphenyl)imidazo[1,5-a]pyridine Cl]BF4 (Ir-3), was developed as a novel antiplatelet drug. Ir-3 exerted more potent inhibitory activity on platelet aggregation stimulated by collagen compared with other agonists, including thrombin. In collagen-activated platelets, Ir-3 also inhibited adenosine trisphosphate release, intracellular Ca+2 mobilization and surface P-selectin expression, as well as the phosphorylation of phospholipase Cγ2 (PLCγ2), protein kinase C (PKC), protein kinase B (Akt) and c-Jun N-terminal kinase (JNK) 1, but not p38 mitogen-activated protein kinase or extracellular signal-regulated kinases. Ir-3 did not markedly affect phorbol 12, 13-dibutyrate-stimulated platelet aggregation. 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-3-mediated inhibition of platelet aggregation. Furthermore, Ir-3 had no considerable diminishing effects on OH radical signals in collagen-stimulated platelets or Fenton reaction solution. In conclusion, Ir-3 serves a novel function in the inhibition of platelet aggregation through inhibiting the PLCγ2-PKC cascade, and the subsequent suppression of Akt and JNK1 activation. Therefore, Ir-3 may be a potential novel therapeutic agent for the treatment of thromboembolic disorders, or the interplay between platelets and tumor cells which contributes to tumor cell proliferation and progression.