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Calix[4]arene methylenebisphosphonic acids as inhibitors of fibrin polymerization.
MedLine Citation:
PMID:  21294845     Owner:  NLM     Status:  Publisher    
Calix[4]arenes bearing two or four methylenebisphosphonic acid groups at the macrocyclic upper rim have been studied with regard to their effects on fibrin polymerization. The most potent inhibitor proved to be calix[4]arene tetrakis-methylene-bis-phosphonic acid C-192, in which case the maximum rate of fibrin polymerization in fibrinogen+thrombin reaction decreased by 50% at concentrations of 0.52 · 10(-6) M (IC(50) ). At this concentration the molar ratio of the compound to fibrinogen was 1.7 to 1. For the case of desAABB fibrin polymerization, the IC(50) was 1.26 · 10(-6) M at a molar ratio of C-192 to fibrin monomer of 4 to 1. Dipropoxycalix[4]arene bis-methylene-bis-phosphonic acid (C-98) inhibited of fibrin desAABB polymerization with IC(50) = 1.31 · 10(-4) M. We hypothesized that C-192 blocks fibrin formation by combining with polymerization site "A" (Aα17-19), which ordinarily initiates protofibril formation in a "knob-hole" manner. This suggestion was confirmed by an HPLC assay, which showed a host-guest inclusion complex of C-192 with the synthetic peptide Gly-Pro-Arg-Pro, an analogue of "site "A". Further confirmation that the inhibitor was acting at the initial step of the reaction was obtained by electron microscopy, no evidence of protofibril formation being evident. Calixarene C-192 also doubled both the prothrombin time and the activated partial thromboplastin time in normal human blood plasma at concentrations of 7.13 · 10(-5) M and 1.10 · 10(-5) M, respectively. These experiments demonstrate that calix[4]arene tetrakis-methylene-bis-phosphonic acid is a specific inhibitor of fibrin polymerization and blood coagulation and can be used for the design of a new class of antithrombotic agents.
E V Lugovskoi; P G Gritsenko; T A Koshel; I O Koliesnik; S O Cherenok; O I Kalchenko; V I Kalchenko; S V Komisarenko
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-2-5
Journal Detail:
Title:  The FEBS journal     Volume:  -     ISSN:  1742-4658     ISO Abbreviation:  -     Publication Date:  2011 Feb 
Date Detail:
Created Date:  2011-2-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101229646     Medline TA:  FEBS J     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Journal compilation © 2011 Federation of European Biochemical Societies.
Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine, Kyiv, Ukraine, 9 Leontovicha Street, 01601, Kyiv, Ukraine. Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, 02660, Kyiv-94, Ukraine.
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