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Membrane‐permeable Triphosphate Prodrugs of Nucleoside Analogues
Author(s) -
Gollnest Tristan,
Dinis de Oliveira Thiago,
Rath Anna,
Hauber Ilona,
Schols Dominique,
Balzarini Jan,
Meier Chris
Publication year - 2016
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201511808
Subject(s) - prodrug , nucleoside , nucleoside triphosphate , chemistry , biochemistry , nucleotide , nucleoside diphosphate kinase , thymidine , enzyme , adenosine triphosphate , phosphonate , dna , gene
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 (Tri PPP ro‐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 Tri PPP ro‐compounds of some HIV‐inactive nucleoside analogues showed marked anti‐HIV activity. For cellular uptake studies, a fluorescent Tri PPP ro‐compound was prepared that delivered the triphosphorylated metabolite to intact CEM cells.