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Ir-6: a novel iridium (III) organometallic derivative that inhibits human platelet activation

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Document pages: 14 pages

Abstract: It is reported that platelet activation plays a major role in arterial thrombosis, cancer metastasis and progression. Recently, we developed a new IR (III) - based compound, [IR (CP) 1 - (2-pyridyl) - 3 - (4-dimethylaminophenyl) imidazole [1,5-a] pyridine CL] BF4 or ir-6, and evaluated its effectiveness as an antiplatelet drug. Ir-6 has higher efficacy on collagen stimulated human platelet aggregation. Ir-6 also inhibited ATP release, intracellular Ca2 + mobilization, P-selectin expression and phospholipase C in collagen activated platelets γ 2(PLC γ 2) , protein kinase C (PKC), v-akt mouse thymoma virus oncogene (Akt) protein kinase B and mitogen activated protein kinase (MAPK). Adenylate cyclase inhibitor sq22536 and guanylate cyclase inhibitor 1H - [1,,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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