5056 Journal of Medicinal Chemistry, 2007, Vol. 50, No. 21
Letters
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Legname, G.; Prusiner, S. B.; Cohen, F. E. Structure-activity
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(21) Milhavet, O.; McMahon, H. E.; Rachidi, W.; Nishida, N.; Katamine,
S.; Mange, A.; Arlotto, M.; Casanova, D.; Riondel, J.; Favier, A.;
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(22) Nakagawa, H.; Ohyama, R.; Kimata, A.; Suzuki, T.; Miyata, N.
Hydroxyl radical scavenging by edaravone derivatives: Efficient
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tramolecular base. Bioorg. Med. Chem. Lett. 2006, 16, 5939-5942.
(23) Ono, S.; Okazaki, K.; Sakurai, M.; Inoue, Y.; Density functional study
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(24) Fukuuchi, T.; Doh-ura, K.; Yoshihara, S.; Ohta, S. Metal complexes
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drug. Bioorg. Med. Chem. Lett. 2006, 16, 5982-5987.
(25) Vosburgh, W. C.; Cooper, G. R. Complex ions. I. The identification
of complex ions in solution by spectrophotometric measurements. J.
Am. Chem. Soc. 1941, 63, 437-442.
like activity of Cu(II) itself. A total of 1 mM of Cu(II) inhibited
WST-1 formazan formation by 6.7%.
For all measured compounds, SOD-like activity was found
to be very weak. Furthermore, because nonantiprion compounds,
such as 6 and 15, showed comparable activity with 13 and were
more effective than compounds 7 and 14, SOD-like activity may
not be correlated with antiprion activity of these compounds.
In conclusion, we found that some pyrazolone compounds
derivatized from edaravone have the ability to inhibit the
accumulation of PrP-res, and 3-(4-nitrophenyl) compound 13
had remarkable activity (IC50 ) 3 nM). To obtain information
about their action mechanism, we investigated their oxidation
potentials, copper-complexing, and SOD-like activity. Findings
from these experiments suggest that these properties have little
correlation with activity.
Further active antiprion derivatives and the mechanistic
studies are under investigation.
Acknowledgment. We thank Dr. K. Doh-ura for kindly
providing ScN2a and F3 cell lines for us. This work was
supported in part by Grants-in-Aid for Scientific Research (No.
17590089 for H.N.) from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan.
Supporting Information Available: Experimental details of
the synthesis and characterization data for all compounds and
analytical methodologies. This information is available free of
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