Abstract
The development of nucleoside triphosphate prodrugs is one option to apply nucleoside reverse transcriptase inhibitors. Herein, we report the synthesis and evaluation of d4TTP analogues, in which the γ‐phosphate was modified covalently by lipophilic alkyl residues, and acyloxybenzyl prodrugs of these γ‐alkyl‐modified d4TTPs, with the aim of delivering of γ‐alkyl‐d4TTP into cells. Selective formation of γ‐alkyl‐d4TTP was proven with esterase and in CD4+‐cell extracts. In contrast to d4TTP, γ‐alkyl‐d4TTPs proved highly stable against dephosphorylation. Primer extension assays with HIV reverse transcriptase (RT) and DNA‐polymerases α, β or γ showed that γ‐alkyl‐d4TTPs were substrates for HIV‐RT only. In antiviral assays, compounds were highly potent inhibitors of HIV‐1 and HIV‐2 also in thymidine‐kinase‐deficient T‐cell cultures (CEM/TK−). Thus, the intracellular delivery of such γ‐alkyl‐nucleoside triphosphates may potentially lead to nucleoside triphosphates with a higher selectivity towards the viral polymerase that can act in virus‐infected cells.
Highlights
Over the last decades a variety of nucleoside analogues have been applied in antitumor and antiviral therapy and still play an important role in combatting HIV, herpes viruses, and hepatitis B and hepatitis C viral infections.[1,2] The targets of these nucleoside analogue drugs are the virus-encoded DNAor RNA polymerases, such as HIV reverse transcriptase (RT)[3,4] or the hepatitis C-encoded RNA-dependent RNApolymerase NS5B.[5]
We proved for d4T 1 and other nucleoside analogues that the corresponding TriPPPro compounds even retained pronounced anti-HIV activity in thymidine-kinase-deficient T
The aim was the intracellular delivery of g-alkyl-nucleoside triphosphates (NTPs) 7 (Figure 1)
Summary
Over the last decades a variety of nucleoside analogues have been applied in antitumor and antiviral therapy and still play an important role in combatting HIV, herpes viruses, and hepatitis B and hepatitis C viral infections.[1,2] The targets of these nucleoside analogue drugs are the virus-encoded DNAor RNA polymerases, such as HIV reverse transcriptase (RT)[3,4] or the hepatitis C-encoded RNA-dependent RNApolymerase NS5B.[5]. The antiviral activity of nucleoside analogues, such as 3’-deoxy-2’,3’-didehydrothymidine 1 (d4T), a thymidine (3) analogue, is dependent on the intracellular phosphorylation by host cell kinases into their nucleoside triphosphates (NTPs), for example, d4TTP 2 t via the nucleoside mono- (2 m, here: d4TMP) and the diphosphate (2 d, here: d4TDP).[7,8] This stepwise transformation into the corresponding triphosphates, such as 2 t, often occurs insufficiently by the involved kinases due to structural differences to the natural nucleosides (for example, TMP 4 m, TDP 4 d, and TTP 4 t). The aim was the intracellular delivery of g-alkyl-NTPs 7 (Figure 1)
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