Antiplatelet Effect and Selective Binding to Cyclooxygenase by Molecular Docking Analysis of 3-Alkylaminopropoxy-9,10-anthraquinone Derivatives

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), c...

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Bibliographic Details
Published in:Biological & Pharmaceutical Bulletin 2008/08/01, Vol.31(8), pp.1547-1551
Main Authors: Gan, Kim-Hong, Teng, Chi-Huang, Lin, Hsien-Cheng, Chen, Kun-Tze, Chen, Yu-Chian, Hsu, Mei-Feng, Wang, Jih-Pyang, Teng, Che-Ming, Lin, Chun-Nan
Format: Article
Language:English
Subjects:
3-alkylaminopropoxy-9,10-anthraquinone
Animals
Anthraquinones - chemical synthesis
Anthraquinones - pharmacology
antiplatelet effect
Aspirin - pharmacology
cyclooxygenase
Cyclooxygenase 1 - metabolism
Cyclooxygenase Inhibitors - chemical synthesis
Cyclooxygenase Inhibitors - pharmacology
Data Interpretation, Statistical
Epinephrine - pharmacology
In Vitro Techniques
Models, Molecular
Platelet Aggregation - drug effects
Platelet Aggregation Inhibitors - chemical synthesis
Platelet Aggregation Inhibitors - pharmacology
Prostaglandin-Endoperoxide Synthases - metabolism
Protein Binding
Protein Conformation
Rabbits
Substrate Specificity
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Summary: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 μM). 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)H2 in the active site of COX-1.
ISSN:0918-6158
1347-5215
DOI:10.1248/bpb.31.1547