title: N4-acyl-modified D-2',3'-dideoxy-5-fluorocytidine nucleoside analogues with improved antiviral activity.
abstract: 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 N4-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, N4-substitutions improved the anti-HIV-1 activity markedly without increasing the cytotoxicity. In the D4-nucleosides series, some of the substituents at the N4-position enhanced the anti-HIV-1 activity with a modest increase in the cytotoxicity. The most potent and selective N4-modified nucleoside for the D2-series was N4-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, N4-p-bromobenzoyl-D4FC was 12-fold more potent in MT-2 cells compared to the parent nucleoside D-D4FC. All eight N4-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 N4-modification especially in the D2-nucleoside series containing the N4-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 N4-acyl-D4FC analogues in different cells, the levels of the 5'-triphosphate nucleotide did not correlate with the cell-derived 90% effective antiviral concentrations (EC90), suggesting that a direct interaction of the triphosphates of these N4-acyl nucleosides was involved in the antiviral activity.
authors.affiliation: Pharmasset, Inc., Tucker, Ga., USA. jshi@pharmasset.com
authors.forename: Junxing
authors.initials: J
authors.lastname: Shi
authors.forename: Judy S
authors.initials: JS
authors.lastname: Mathew
authors.forename: Phillip M
authors.initials: PM
authors.lastname: Tharnish
authors.forename: Suguna
authors.initials: S
authors.lastname: Rachakonda
authors.forename: S Balakrishna
authors.initials: SB
authors.lastname: Pai
authors.forename: Marjorie
authors.initials: M
authors.lastname: Adams
authors.forename: Jason P
authors.initials: JP
authors.lastname: Grier
authors.forename: Karen
authors.initials: K
authors.lastname: Gallagher
authors.forename: Hangchun
authors.initials: H
authors.lastname: Zhang
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Wu
authors.forename: Guoen
authors.initials: G
authors.lastname: Shi
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.forename: Susan
authors.initials: S
authors.lastname: Erickson-Viitanen
authors.forename: Lieven
authors.initials: L
authors.lastname: Stuyver
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Otto
authors.forename: Kyoichi A
authors.initials: KA
authors.lastname: Watanabe
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000187:drug effects; D006515:Hepatitis B virus / Q000187:drug effects; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D014709:Vero Cells; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D000998:Antiviral Agents; D016047:Zalcitabine; C099405:dexelvucitabine