Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation
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 anti...
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| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2018-01-01
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| Series: | Bioinorganic Chemistry and Applications |
| Online Access: | http://dx.doi.org/10.1155/2018/8291393 |
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| author | Ren-Shi Shyu Themmila Khamrang Joen-Rong Sheu Chih-Wei Hsia Marappan Velusamy Chih-Hsuan Hsia Duen-Suey Chou Chao-Chien Chang |
| author_facet | Ren-Shi Shyu Themmila Khamrang Joen-Rong Sheu Chih-Wei Hsia Marappan Velusamy Chih-Hsuan Hsia Duen-Suey Chou Chao-Chien Chang |
| author_sort | Ren-Shi Shyu |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-ee7fc18b6dd24ff6bccad17f2d4ed3c4 |
| institution | Kabale University |
| issn | 1565-3633 1687-479X |
| language | English |
| publishDate | 2018-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Bioinorganic Chemistry and Applications |
| spelling | doaj-art-ee7fc18b6dd24ff6bccad17f2d4ed3c42025-02-03T01:30:53ZengWileyBioinorganic Chemistry and Applications1565-36331687-479X2018-01-01201810.1155/2018/82913938291393Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet ActivationRen-Shi Shyu0Themmila Khamrang1Joen-Rong Sheu2Chih-Wei Hsia3Marappan Velusamy4Chih-Hsuan Hsia5Duen-Suey Chou6Chao-Chien Chang7Division of Nephrology, Department of Internal Medicine, Min-Sheng General Hospital, Taoyuan 330, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Chemistry, North Eastern Hill University, Shillong 793022, IndiaGraduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanDepartment of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, TaiwanPlatelet 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.http://dx.doi.org/10.1155/2018/8291393 |
| spellingShingle | Ren-Shi Shyu Themmila Khamrang Joen-Rong Sheu Chih-Wei Hsia Marappan Velusamy Chih-Hsuan Hsia Duen-Suey Chou Chao-Chien Chang Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation Bioinorganic Chemistry and Applications |
| title | Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation |
| title_full | Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation |
| title_fullStr | Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation |
| title_full_unstemmed | Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation |
| title_short | Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation |
| title_sort | ir 6 a novel iridium iii organometallic derivative for inhibition of human platelet activation |
| url | http://dx.doi.org/10.1155/2018/8291393 |
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