AntiViral Pyridinone Nucleoside DeriVatiVes
Journal of Medicinal Chemistry, 2006, Vol. 49, No. 1 49
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Chem. 1999, 42, 4814-4823. (c) Liu, Z. D.; Khodr, H.; Liu, D. Y.;
Lu, S. L.; Hider R. C. Design, synthesis and evaluation of N-basic
substituted 3-hydroxypyridin-4-ones: orally active iron chelators with
lysosomotrophic potential. J. Pharm. Pharmacol. 2000, 52, 263-
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(III)-Selective Chelators. Med. Res. ReV. 2002, 22, 26-64.
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Anti-HSV Assays and Effect of the Compounds on Uninfected
Cells. HEL cells were grown to confluency in microtiter trays and
were inoculated with one of the different HSV strains at 100 times
the 50% cell culture infective dose. Compounds, either alone or in
combination, were added after a 2-h virus adsorption period. The
virus-induced cytopathic effect (CPE) was recorded microscopically
at 2 to 3 days postinfection and were expressed as percentage of
the untreated controls. The 50% effective concentrations (EC50)
were derived from graphical plots. The minimal toxic concentration
(MTC) was defined as the minimal concentration that resulted in a
microscopically detectable alteration of cell morphology. The MTC
was determined in uninfected confluent cultures of HEL cells that
were incubated, akin to the cultures used for the antiviral assays,
with serial dilutions of the compounds for the same period. Cultures
were inspected microscopically for alteration of cell morphology.
Anti-HIV Assays. The methodology has been described previ-
ously.22 In brief, CEM cells (4.5 × 105 cells per mL) were
suspended in fresh culture medium and infected with HIV-1(IIIB)
or HIV-2(ROD) at 100 CCID50 per mL of cell suspension. Then,
100 µL of the infected cell suspension was transferred to microplate
wells, mixed with 100 µL of the appropriate dilutions of the test
compounds, and further incubated at 37 °C. After 4 to 5 days, giant
cell formation was recorded microscopically in the CEM cell
cultures. The 50% effective concentration (EC50) corresponds to
the compound concentrations required to prevent syncytium forma-
tion by 50% in the virus-infected CEM cell cultures. The 50%
cytostatic concentration (CC50) corresponds to the compound
concentration required to inhibit cell proliferation by 50%.
Acknowledgment. We wish to thank Dr. Robert Faure
(Universite´ d’Aix-Marseille III, St. Je´roˆme, Marseille, France)
for his expertise in conducting NMR experiments, Xiao Kong
and Tao Zhou (King’s College) for their technical assistance in
determining the physicochemical characteristics of several of
the compounds described in this report, and Mrs. Miette Stuyck,
Mrs. Ann Absillis, Mrs. Anita Vanlierde, and Mrs. Frieda De
Meyer (Rega Institute) for excellent technical assistance.
Financial support has been obtained from the European Com-
mission (QLRT-CT-2000-30291) and the Foundation for Sci-
entific Research G-0267-04.
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Ether Hydrolysis. J. Org. Chem. 1977, 42, 3761-3764. (b) Huang,
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methyl)-1,3-oxathiolan-5-yl]cytosine and its (()-trans isomer. Nu-
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Supporting Information Available: Elemental analysis and
spectroscopic data. This material is available free of charge via
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Nucleoside and Nucleotide Analogues from Amino Acids:
A
Convenient Approach to a PMEA-PMPA Hybrid. Tetrahedron. 2000,
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F.; Brinckmann, U.; Gu¨tschow, M.; Eger, K. Synthesis of Acyclic
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