Membrane‐permeable Triphosphate Prodrugs of Nucleoside Analogues

Abstract

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 (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.