title: Nucleoside mono- and diphosphate prodrugs of 2',3'-dideoxyuridine and 2',3'-dideoxy-2',3'-didehydrouridine.
abstract: Despite their close structural similarity to nucleoside analogues such as the anti-HIV drugs AZT and d4T, 2',3'-dideoxyuridine (ddU) and 2',3'-dideoxy-2',3'-didehydrouridine (d4U) are entirely inactive against HIV in their nucleoside form. However, it has been shown that the corresponding triphosphates of these two nucleosides can effectively block HIV reverse transcriptase. Herein we report on two types of nucleotide prodrugs (cycloSal and DiPPro nucleotides) of ddU and d4U to investigate their ability to overcome insufficient intracellular phosphorylation, which may be the reason behind their low anti-HIV activity. The release of the corresponding mono- and diphosphates from these compounds was demonstrated by hydrolysis studies in phosphate buffer (pH 7.3) and human CD4 (+) T-lymphocyte CEM cell extracts. Surprisingly, however, these compounds showed low or no anti-HIV activity in tests with human CD4 (+) T-lymphocyte CEM cells. Studies of the conversion of ddUDP and d4UDP into their triphosphate metabolites by nucleoside diphosphate kinase (NDPK) showed nearly no conversion of either diphosphate, which may be the reason for low intracellular triphosphate levels that result in low antiviral activity.
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146 Hamburg (Germany).
authors.forename: Florian
authors.initials: F
authors.lastname: Pertenbreiter
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011756:Diphosphates / Q000737:chemistry; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006207:Half-Life; D006801:Humans; D006868:Hydrolysis; D009701:Nucleoside-Diphosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009705:Nucleosides / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D011756:Diphosphates; D009705:Nucleosides; D011355:Prodrugs; C058925:2',3'-didehydro-2',3'-dideoxyuridine; C059513:2',3'-dideoxyuridine; D009701:Nucleoside-Diphosphate Kinase
keywords: HIV; antiviral agents; bioreversible protection; drug delivery; nucleosides; prodrugs