{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,23]],"date-time":"2026-04-23T11:14:32Z","timestamp":1776942872000,"version":"3.51.4"},"reference-count":47,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,19]],"date-time":"2018-11-19T00:00:00Z","timestamp":1542585600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004319","name":"Shin Kong Wu Ho-Su Memorial Hospital","doi-asserted-by":"publisher","award":["SKH-8302-104-DR-23; SKH-8302-105-DR-21"],"award-info":[{"award-number":["SKH-8302-104-DR-23; SKH-8302-105-DR-21"]}],"id":[{"id":"10.13039\/501100004319","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004663","name":"Ministry of Science and Technology of Taiwan","doi-asserted-by":"publisher","award":["MOST 104-2622-B-038-003, MOST 104-2320-B-038-045-MY2, MOST 106-2320-B-038-012, MOST 106-2320-B-038-049-MY3"],"award-info":[{"award-number":["MOST 104-2622-B-038-003, MOST 104-2320-B-038-045-MY2, MOST 106-2320-B-038-012, MOST 106-2320-B-038-049-MY3"]}],"id":[{"id":"10.13039\/501100004663","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shin Kong Wu Ho-Su Memorial Hospital\u2013Taipei Medical University","award":["SKH-TMU-104-05, SKH-TMU-105-02"],"award-info":[{"award-number":["SKH-TMU-104-05, SKH-TMU-105-02"]}]},{"DOI":"10.13039\/501100004700","name":"Taipei Medical University","doi-asserted-by":"publisher","award":["DP2-107-21121-N-02"],"award-info":[{"award-number":["DP2-107-21121-N-02"]}],"id":[{"id":"10.13039\/501100004700","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the University Grants Commission, India","award":["MRP-MAJOR-CHEM-2013-5144; 69\/2014 F. No. 10-11\/12UGC"],"award-info":[{"award-number":["MRP-MAJOR-CHEM-2013-5144; 69\/2014 F. No. 10-11\/12UGC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Platelets play a major role in hemostatic events and are associated with various pathological events, such as arterial thrombosis and atherosclerosis. Iridium (Ir) compounds are potential alternatives to platinum compounds, since they exert promising anticancer effects without cellular toxicity. Our recent studies found that Ir compounds show potent antiplatelet properties. In this study, we evaluated the in vitro antiplatelet, in vivo antithrombotic and structure\u2013activity relationship (SAR) of newly synthesized Ir complexes, Ir-1, Ir-2 and Ir-4, in agonists-induced human platelets. Among the tested compounds, Ir-1 was active in inhibiting platelet aggregation induced by collagen; however, Ir-2 and Ir-4 had no effects even at their maximum concentrations of 50 \u03bcM against collagen and 500 \u03bcM against U46619-induced aggregation. Similarly, Ir-1 was potently inhibiting of adenosine triphosphate (ATP) release, calcium mobilization ([Ca2+]i) and P-selectin expression induced by collagen-induced without cytotoxicity. Likewise, Ir-1 expressively suppressed collagen-induced Akt, PKC, p38MAPKs and JNK phosphorylation. Interestingly, Ir-2 and Ir-4 had no effect on platelet function analyzer (PFA-100) collagen-adenosine diphosphate (C-ADP) and collagen-epinephrine (C-EPI) induced closure times in mice, but Ir-1 caused a significant increase when using C-ADP stimulation. Other in vivo studies revealed that Ir-1 significantly prolonged the platelet plug formation, increased tail bleeding times and reduced the mortality of adenosine diphosphate (ADP)-induced acute pulmonary thromboembolism in mice. Ir-1 has no substitution on its phenyl group, a water molecule (like cisplatin) can replace its chloride ion and, hence, the rate of hydrolysis might be tuned by the substituent on the ligand system. These features might have played a role for the observed effects of Ir-1. These results indicate that Ir-1 may be a lead compound to design new antiplatelet drugs for the treatment of thromboembolic diseases.<\/jats:p>","DOI":"10.3390\/ijms19113641","type":"journal-article","created":{"date-parts":[[2018,11,21]],"date-time":"2018-11-21T11:23:27Z","timestamp":1542799407000},"page":"3641","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Structure\u2013Activity Relationship Study of Newly Synthesized Iridium-III Complexes as Potential Series for Treating Thrombotic Diseases"],"prefix":"10.3390","volume":"19","author":[{"given":"Chih-Hao","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Schools of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Wei","family":"Hsia","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanasekaran","family":"Jayakumar","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joen-Rong","family":"Sheu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Schools of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chih-Hsuan","family":"Hsia","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Themmila","family":"Khamrang","sequence":"additional","affiliation":[{"name":"Department of Chemistry, North Eastern Hill University, Shillong 793022, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yen-Jen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Schools of Medicine, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"},{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Manjunath","family":"Manubolu","sequence":"additional","affiliation":[{"name":"Department of Evolution, Ecology and Organismal Biology, Ohio State University, Columbus, OH 43212, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yi","family":"Chang","sequence":"additional","affiliation":[{"name":"Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, No. 250, Wu Hsing St., Taipei 110, Taiwan"},{"name":"Department of Anesthesiology, Shin Kong Wu Ho-Su Memorial Hospital, No. 95, Wen Chang Rd., Taipei 111, Taiwan"},{"name":"School of Medicine, Fu-Jen Catholic University, No. 510, Zhong Zheng Rd, Xin Zhuang Dist., New Taipei City 242, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"283","DOI":"10.3122\/jabfm.2015.02.140189","article-title":"Diagnosis and management of acute coronary syndrome: An evidence-based update","volume":"28","author":"Smith","year":"2015","journal-title":"J. Am. Board Fam. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/nrcardio.2014.156","article-title":"Novel antiplatelet agents in acute coronary syndrome","volume":"12","author":"Franchi","year":"2015","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1160\/TH08-01-0056","article-title":"Clinical implications of aspirin resistance","volume":"100","author":"Zimmermann","year":"2008","journal-title":"Thromb. Haemost."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1007\/s11886-006-0063-5","article-title":"Antiplatelet resistance with aspirin and clopidogrel: Is it real and does it matter?","volume":"8","author":"Chen","year":"2006","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_5","first-page":"CD001342","article-title":"Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin","volume":"3","author":"Algra","year":"2006","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/ijc.2910600324","article-title":"The effect of platelets on invasiveness and protease production of human mammary tumor cells","volume":"60","author":"Belloc","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1714","DOI":"10.1172\/JCI200422123","article-title":"Platelet-derived lysophosphatidic acid supports the progression of osteolytic bone metastases in breast cancer","volume":"114","author":"Boucharaba","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10585-009-9299-y","article-title":"Inhibition of metastasis in a murine 4T1 breast cancer model by liposomes preventing tumor cell-platelet interactions","volume":"27","author":"Wenzel","year":"2010","journal-title":"Clin. Exp. Metast."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1097\/CRD.0b013e318189a701","article-title":"Prasugrel: A new antiplatelet drug for the prevention and treatment of cardiovascular disease","volume":"16","author":"Koo","year":"2008","journal-title":"Cardiol. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"637","DOI":"10.2147\/VHRM.S2691","article-title":"Antiplatelet drugs in cardiological practice: Established strategies and new developments","volume":"4","author":"Sohn","year":"2008","journal-title":"Vasc. Health Risk Manag."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1021\/jm100020w","article-title":"Organometallic anticancer compounds","volume":"54","author":"Gasser","year":"2011","journal-title":"Med. Chem."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12847","DOI":"10.1039\/c2dt31654d","article-title":"Novel C, N-chelate rhodium (III) and iridium (III) antitumor complexes incorporating a lipophilic steroidal conjugate and their interaction with DNA","volume":"41","author":"Ruiz","year":"2012","journal-title":"Dalton Trans."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.1021\/ar400266c","article-title":"Organoiridium complexes: Anticancer agents and catalysts","volume":"47","author":"Liu","year":"2014","journal-title":"ACC Chem. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.biomaterials.2014.10.070","article-title":"Phosphorescent iridium (III)-bis-N-heterocyclic carbene complexes as mitochondria-targeted theranostic and photodynamic anticancer agents","volume":"39","author":"Li","year":"2015","journal-title":"Biomaterials"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Hsia, C.W., Velusamy, M., Tsao, J.T., Hsia, C.H., Chou, D.S., Jayakumar, T., Lee, L.W., Li, J.Y., and Sheu, J.R. (2017). New Therapeutic Agent against Arterial Thrombosis: An Iridium (III)-Derived Organometallic Compound. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18122616"},{"key":"ref_16","first-page":"2589","article-title":"Novel iridium (III) -derived organometallic compound for the inhibition of human platelet activation","volume":"41","author":"Shyu","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Shyu, R.S., Khamrang, T., Sheu, J.R., Hsia, C.W., Velusamy, M., Hsia, C.H., Chou, D.S., and Chang, C.C. (2018). Ir-6: A Novel Iridium (III) Organometallic Derivative for Inhibition of Human Platelet Activation. Bioinorg. Chem. Appl.","DOI":"10.1155\/2018\/8291393"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1042\/bj2880925","article-title":"Cytosolic calcium as a second messenger for collagen-induced platelet responses","volume":"288","author":"Smith","year":"1992","journal-title":"Biochem. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3352","DOI":"10.1073\/pnas.061615598","article-title":"Heparin and cancer revisited: Mechanistic connections involving platelets, P-selectin, carcinoma mucins, and tumor metastasis","volume":"98","author":"Borsig","year":"2001","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2007","DOI":"10.1111\/j.1538-7836.2008.03169.x","article-title":"Mitogen-activated protein kinases in hemostasis and thrombosis","volume":"6","author":"Adam","year":"2008","journal-title":"J. Thromb. Haemost."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1046\/j.1538-7836.2003.00070.x","article-title":"Quantification of ADP and ATP receptor expression in human platelets","volume":"1","author":"Wang","year":"2003","journal-title":"J. Thromb. Haemost."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1111\/j.1538-7836.2012.04837.x","article-title":"The unique contribution of ion channels to platelet and megakaryocyte function","volume":"10","year":"2012","journal-title":"J. Thromb. Haemost."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1182\/blood-2011-10-386052","article-title":"Platelet Ca2+ responses coupled to glycoprotein VI and Toll-like receptors persist in the presence of endothelial-derived inhibitors: Roles for secondary activation of P2X1 receptors and release from intracellular Ca2+ stores","volume":"119","author":"Fung","year":"2012","journal-title":"Blood"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1517\/14728222.11.8.1103","article-title":"P-selectin: A common therapeutic target for cardiovascular disorders, inflammation and tumour metastasis","volume":"11","author":"Ludwig","year":"2007","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"33","DOI":"10.2217\/fca-2016-0054","article-title":"Novel strategies for assessing platelet reactivity","volume":"13","author":"Alghatani","year":"2017","journal-title":"Future Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.transci.2009.07.001","article-title":"Preparation, storage and quality control of platelet concentrates","volume":"41","author":"Tynngard","year":"2009","journal-title":"Transfus. Apher. Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1042\/bst0320387","article-title":"Phosphoinositide 3-kinases and the regulation of platelet function","volume":"32","author":"Jackson","year":"2014","journal-title":"Biochem. Soc. Trans."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"38903","DOI":"10.1074\/jbc.M405314200","article-title":"Calmodulin-mediated activation of Akt regulates survival of c-Myc-overexpressing mouse mammary carcinoma cells","volume":"279","author":"Deb","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1182\/blood-2003-10-3428","article-title":"Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice","volume":"104","author":"Chen","year":"2004","journal-title":"Blood"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"5478","DOI":"10.1074\/jbc.M609881200","article-title":"Protease-activating receptor-4 induces full platelet spreading on a fibrinogen matrix: Involvement of ERK2 and p38 and Ca2+ mobilization","volume":"282","author":"Mazharian","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4083","DOI":"10.1182\/blood-2009-07-233932","article-title":"Platelet JNK1 is involved in secretion and thrombus formation","volume":"115","author":"Adam","year":"2010","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/35065000","article-title":"Mammalian MAP kinase signalling cascades","volume":"410","author":"Chang","year":"2001","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1055\/s-0029-1145254","article-title":"Clinical utility of the PFA-100","volume":"34","author":"Favaloro","year":"2008","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1179\/102453308X315834","article-title":"Platelet function testing in uraemic patients","volume":"13","author":"Ho","year":"2008","journal-title":"Hematology"},{"key":"ref_35","first-page":"E514","article-title":"Assessment of PFA-100 system for the measurement of bleeding time in oral surgery","volume":"11","author":"Juzgado","year":"2006","journal-title":"Med. Oral Patol. Oral Cir. Bucal."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.5402\/2012\/839242","article-title":"The Platelet function analyzer (PFA-100) as a screening tool in neurosurgery","volume":"2012","author":"Karger","year":"2012","journal-title":"ISRN Hematol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1111\/jth.13919","article-title":"Platelet collagen receptor Glycoprotein VI-dimer recognizes fibrinogen and fibrin through their D-domains, contributing to platelet adhesion and activation during thrombus formation","volume":"16","author":"Induruwa","year":"2018","journal-title":"J. Thromb. Haemost."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"6858","DOI":"10.1021\/jm060596m","article-title":"Structure-Activity Relationships for cytotoxic ruthenium(II) arene complexes containing N,N-, N,O-, and O,O-chelating ligands","volume":"49","author":"Habtemariam","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1992","DOI":"10.4315\/0362-028X-65.12.1992","article-title":"Platelet aggregation inhibitory activity of bovine, ovine, and caprine \u03ba-casein macropeptides and their tryptic hydrolysates","volume":"65","author":"Manso","year":"2002","journal-title":"J. Food. Prot."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"279","DOI":"10.1016\/0167-4889(92)90148-5","article-title":"Inhibition of platelet adhesion and thrombus formation on a collagen-coated surface by novel carbamoylpiperidine antiplatelet agents","volume":"1137","author":"Alevriadou","year":"1992","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2353","DOI":"10.1021\/jo047853k","article-title":"Highly efficient and direct heterocyclization of dipyridyl ketone to N, N-bidentate ligands","volume":"70","author":"Wang","year":"2005","journal-title":"J. Org. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1002\/9780470132524.ch16","article-title":"(\u03b76-Hexa methylbenzene) ruthenium complexes","volume":"21","author":"Bennett","year":"1982","journal-title":"Inorg. Synth."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1055\/s-0037-1613907","article-title":"Mechanisms involved in the antiplatelet activity of Staphylococcus aureus lipoteichoic acid in human plalets","volume":"83","author":"Sheu","year":"2000","journal-title":"Thromb. Haemost."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1067\/mlc.2001.117406","article-title":"Platelet function analyzer (PFA100): A tool to quantify congenital or acquired platelet dysfunction","volume":"138","author":"Jilma","year":"2001","journal-title":"J. Lab. Clin. Med."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1096\/fj.07-9574LSF","article-title":"Dose translation from animal to human studies revisited","volume":"22","author":"Nihal","year":"2008","journal-title":"FASEB J."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1478","DOI":"10.1016\/j.bcp.2013.02.027","article-title":"Hinokitiol inhibits platelet activation ex vivo and thrombus formation in vivo","volume":"85","author":"Lin","year":"2013","journal-title":"Biochem. Pharmacol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1007\/s00109-011-0800-0","article-title":"Anovelroleofandrographolide, an NF-\u03baB inhibitor, on inhibition of platelet activation: The pivotal mechanisms of endothelial nitric oxide synthase\/cyclic GMP","volume":"89","author":"Lu","year":"2011","journal-title":"J. Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3641\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T15:30:37Z","timestamp":1760196637000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3641"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,19]]},"references-count":47,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113641"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113641","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,19]]}}}