title: Antiplatelet effect and selective binding to cyclooxygenase by molecular docking analysis of 3-alkylaminopropoxy-9,10-anthraquinone derivatives.
abstract: In an effort to develop potent cytotoxic inhibitors of cyclooxygenase (COX), a series of cytotoxic 3-alkylaminopropoxy-9,10-anthraquinone derivatives was screened to evaluate their antiplatelet effect on washed rabbit platelets and human platelet-rich plasma (PRP). Thrombin, arachidonic acid (AA), collagen, and platelet-activating factor (PAF) induced platelet aggregations were potently inhibited by compounds 1, 2, and 3 (each at 300 microM). Of the compounds tested in human PRP, compounds 1, 8, and 10 showed significant inhibition of primary and secondary aggregation induced by epinephrine and had a weak inhibitory effect on cyclooxygenase-1 (COX-1). Molecular docking studies revealed that compounds, 1, 8, and 10 were bound in the active sites of COX-1. This indicated that the antiplatelet effect of these three compounds was partially mediated through the suppression of COX-1 activity and reduced thromboxane formation. It is concluded that the cytotoxic compounds 1, 8, and 10 may interfere the conversion of arachidonic acid to prostaglandin (PG)H(2) in the active site of COX-1.
authors.affiliation: School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Kim-Hong
authors.initials: KH
authors.lastname: Gan
authors.forename: Chi-Huang
authors.initials: CH
authors.lastname: Teng
authors.forename: Hsien-Cheng
authors.initials: HC
authors.lastname: Lin
authors.forename: Kun-Tze
authors.initials: KT
authors.lastname: Chen
authors.forename: Yu-Chian
authors.initials: YC
authors.lastname: Chen
authors.forename: Mei-Feng
authors.initials: MF
authors.lastname: Hsu
authors.forename: Jih-Pyang
authors.initials: JP
authors.lastname: Wang
authors.forename: Che-Ming
authors.initials: CM
authors.lastname: Teng
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Lin
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000138:chemical synthesis* / Q000494:pharmacology*; D001241:Aspirin / Q000494:pharmacology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D003627:Data Interpretation, Statistical; D004837:Epinephrine / Q000494:pharmacology; D066298:In Vitro Techniques; D008958:Models, Molecular; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011817:Rabbits; D013379:Substrate Specificity
chemical_list: D000880:Anthraquinones; D016861:Cyclooxygenase Inhibitors; D010975:Platelet Aggregation Inhibitors; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; D001241:Aspirin; D004837:Epinephrine