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0
the thiocyano group of 9 could also produce 5 -thio-
adenosine which would lead to the formation of a simi-
lar covalent adduct upon enzyme inactivation. Evidence
to support this second mechanistic proposal comes from
References and Notes
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0
inactivation experiments carried out with 5 -thioadeno-
sine. These show that inhibition of the enzyme is
accompanied by the creation of a specific covalently-
linked enzyme adduct (the mass of on each AdoHcy
hydrolase subunit is increased by 269 Da; ESI/MS ana-
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lysis of inactivated enzyme).
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Antiviral Activity
Compounds 5, 7 and 9 were examined for their cyto-
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(
(
E SM) cell cultures, 7 was the most cytotoxic
6
MTC=30 mM) while 5 and 9 presented much lower
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cular stomatitis virus at subtoxic concentration except
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5
0%, MIC=30mM). In vero cell cultures, with the
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1
1
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1
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The preliminary evaluation of a series of 5 -thionucleo-
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´
sides has provided encouraging results that warrant
further mechanistic investigations. Additional studies
are in progress using ESI-MS and nano ESI-MS tech-
niques to confirm the proposed mechanisms and to elu-
cidate the localisation of the possible covalent linkage
induced by AdoHcy hydrolase with 5, 7 and 9.
n
2
2. Glapski, C.; Muzard. M.; Pillard. S.; Guillerm, G.
Unpublished results.
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Acad. Sci. U.S.A. 1985, 82, 4578.
4. The structure of AdoHcy has been extracted from the
2
2
Acknowledgements
Brookhaven Data base (PDB entry 1A7A). Inhibitor 7 has
been built with the molecular modeling software Quanta98. Its
geometry has been optimized using CHARm force field.
25. Momany, F. A.; Rone, R. J. Comput. Chem. 1992, 13,
888.
The authors thank Dr. Christine Lambert (AstraZe-
neca-Reims, Centre de Recherches) for the molecular
modeling work.
25