title: Nucleoside Diphosphate Prodrugs: Nonsymmetric DiPPro-Nucleotides.
abstract: Nonsymmetric DiPPro-nucleotides are described as nucleoside diphosphate (NDP) delivery systems. The concept is to attach different bis(acyloxybenzyl) moieties at the β-phosphate moiety of a NDP. DiPPro compounds bearing two alkanoylbenzyl residues and DiPPro compounds bearing an alkanoylbenzyl or a benzoylbenzyl group as bioreversible prodrug moieties were studied. Compounds bearing short chain alkanoyl esters led to a fast hydrolysis by chemical or enzymatic means. The ester group in the second prodrug group comprised a long lipophilic aliphatic or an aromatic residue. The lipophilicity of this group enabled the prodrug to penetrate the cell membrane. The introduction of two different groups allowed a controlled stepwise removal of the prodrug moieties to achieve a highly selective delivery of the NDP in CEM cell extracts. The compounds were highly active against HIV even in thymidine kinase-deficient CEM cells. Thus, the compounds, although charged at the α-phosphate group, were taken up by the cells and released NDPs.
authors.affiliation: †Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Lina
authors.initials: L
authors.lastname: Weinschenk
authors.affiliation: ‡Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: ‡Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.affiliation: †Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg, Germany.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D009705:Nucleosides / Q000494:pharmacology*; D009711:Nucleotides / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D009711:Nucleotides; D011355:Prodrugs