title: Membrane-permeable Triphosphate Prodrugs of Nucleoside Analogues.
abstract: The metabolic conversion of nucleoside analogues into their triphosphates often proceeds insufficiently. Rate-limitations can be at the mono-, but also at the di- and triphosphorylation steps. We developed a nucleoside triphosphate (NTP) delivery system (TriPPPro-approach). In this approach, NTPs are masked by two bioreversible units at the γ-phosphate. Using a procedure involving H-phosphonate chemistry, a series of derivatives bearing approved, as well as potentially antivirally active, nucleoside analogues was synthesized. The enzyme-triggered delivery of NTPs was demonstrated by pig liver esterase, in human T-lymphocyte cell extracts and by a polymerase chain reaction using a prodrug of thymidine triphosphate. The TriPPPro-compounds of some HIV-inactive nucleoside analogues showed marked anti-HIV activity. For cellular uptake studies, a fluorescent TriPPPro-compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells.
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany.
authors.forename: Tristan
authors.initials: T
authors.lastname: Gollnest
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany.
authors.forename: Thiago
authors.initials: T
authors.lastname: Dinis de Oliveira
authors.affiliation: Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg, Martin-Luther-King-Platz 6, 20146, Hamburg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Rath
authors.affiliation: Heinrich-Pette-Institute, Leibniz Institute of Experimental Virology, Martinistrasse 52, 20251, Hamburg, Germany.
authors.forename: Ilona
authors.initials: I
authors.lastname: Hauber
authors.affiliation: Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, 3000, Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Laboratory of Virology and Chemotherapy, Department of Microbiology and Immunology, Rega Institute for Medical Research, KU 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. chris.meier@chemie.uni-hamburg.de.
authors.forename: Chris
authors.initials: C
authors.lastname: Meier
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002460:Cell Line; D002463:Cell Membrane Permeability; D004950:Esterases / Q000378:metabolism; D006678:HIV / Q000187:drug effects*; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D009705:Nucleosides / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011122:Polyphosphates / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D013552:Swine; D013942:Thymine Nucleotides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D019380:Anti-HIV Agents; D009705:Nucleosides; D011122:Polyphosphates; D011355:Prodrugs; D013942:Thymine Nucleotides; D004950:Esterases; C005692:triphosphoric acid; C024157:thymidine 5'-triphosphate
keywords: biological activity; cell uptake; nucleoside analogues; prodrugs; triphosphate