N 4-Acyl-Modified D-2′,3′-Dideoxy-5-Fluorocytidine Nucleoside Analogues with Improved Antiviral Activity

A series of 2,3-dideoxy (D2) and 2,3-didehydro-2,3-dideoxy (D4) 5-fluorocytosine nucleosides modified with substituted benzoyl, heteroaromatic carbonyl, cycloalkylcarbonyl and alkanoyl at the N 4 -position were synthesized and evaluated for anti-human immunodeficiency virus type 1 (HIV-1) and anti-h...

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Veröffentlicht in:Antiviral chemistry & chemotherapy 2003-04, Vol.14 (2), p.81-90
Hauptverfasser: Shi, Junxing, Mathew, Judy S, Tharnish, Phillip M, Rachakonda, Suguna, Pai, S Balakrishna, Adams, Marjorie, Grier, Jason P, Gallagher, Karen, Zhang, Hangchun, Wu, Jing-Tao, Shi, Guoen, Geleziunas, Romas, Erickson-Viitanen, Susan, Stuyver, Lieven, Otto, Michael J, Watanabe, Kyoichi A, Schinazi, Raymond F
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Sprache:eng
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Zusammenfassung:A series of 2,3-dideoxy (D2) and 2,3-didehydro-2,3-dideoxy (D4) 5-fluorocytosine nucleosides modified with substituted benzoyl, heteroaromatic carbonyl, cycloalkylcarbonyl and alkanoyl at the N 4 -position were synthesized and evaluated for anti-human immunodeficiency virus type 1 (HIV-1) and anti-hepatitis B virus (HBV) activity in vitro. For most D2-nucleosides, N 4 -substitutions improved the anti-HIV-1 activity markedly without increasing the cytotoxicity. In the D4-nucleosides series, some of the substituents at the N 4 -position enhanced the anti-HIV-1 activity with a modest increase in the cytotoxicity. The most potent and selective N 4 -modified nucleoside for the D2-series was N 4 - p-iodobenzoyl-D2FC, which had a 46-fold increase in anti-HIV-1 potency in MT-2 cells compared to the parent nucleoside D-D2FC. In the D4-series, N 4 - p-bromobenzoyl-D4FC was 12-fold more potent in MT-2 cells compared to the parent nucleoside D-D4FC. All eight N 4 - p-halobenzoyl-substituted D2- and D4-nucleosides evaluated against HBV in HepAD38 cells demonstrated equal or greater potency than the two parental compounds, D-D2FC and D-D4FC. The N 4 -modification especially in the D2-nucleoside series containing the N 4 -nicotinoyl, o-nitrobenzoyl and n-butyryl showed a significant reduction in mitochondrial toxicity relative to the parent nucleoside analogue. Although the 5′-triphosphate of the parent compound (D-D4FC-TP) was formed from the N 4 -acyl-D4FC analogues in different cells, the levels of the 5′-triphosphate nucleotide did not correlate with the cell-derived 90% effective antiviral concentrations (EC 90 ), suggesting that a direct interaction of the triphosphates of these N 4 -acyl nucleosides was involved in the antiviral activity.
ISSN:0956-3202
2040-2066
DOI:10.1177/095632020301400203