γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals

Nack, Tobias; Oliveira, Thiago Dinis de; Weber, Stefan; Schols, Dominique; Balzarini, Jan; Meier, Chris

doi:10.1021/acs.jmedchem.0c01293

Cited by 10 publications

(18 citation statements)

References 49 publications

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“…The hydrolysis studies with both γ-hexadecyl NTPs 3 and 11 , γ-hexadecyl-FLTTP prodrug 4 , Tri PPP ro-FLTTP 5 , FLTTP 2 , and TTP were performed under identical conditions in PBS (pH 7.3) and CEM/0 cell extracts as described in our previous studies. ,,, …”

Section: Resultsmentioning

confidence: 99%

“…The hydrolysis studies with both γhexadecyl NTPs 3 and 11, γ-hexadecyl-FLTTP prodrug 4, TriPPPro-FLTTP 5, FLTTP 2, and TTP were performed under identical conditions in PBS (pH 7.3) and CEM/0 cell extracts as described in our previous studies. 10,13,14,21 First, all compounds were hydrolyzed in PBS (pH 7.3) at 37 °C. TriPPPro-FLTTP 5 bearing two identical acyloxybenzyl groups showed half-lives of t 1/2 (1) = 81 h for the cleavage of the first masking group and t 1/2 (2) = 628 h for the second bioreversible group.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…3 J H,F = 20.9 Hz, 2 J H,H = 14.6 Hz, 3 J H,H = 5.6 Hz, H-2a′), 2.42 (dddd, 1H, 3 J H,F = 41.0 Hz, 2 J H,H = 14.0 Hz, 3 J H,H = 9.6 Hz, 4.5 Hz, H-2b′), 1.95 (s, 3H, CH 3 ), 1.69-1.61 (m, 2H, CH 2 -alkyl), 1.38− 1.20 (m, 26H, CH 2 -alkyl), 0.87 (t, 3H, 3 J H,H = 6.9 Hz, CH 3 -alkyl). 13 Thymidine Diphosphate (Tetrabutylammonium Salt) (TDP) 12. TDP 12 was synthesized in analogy to procedures described in the literature, and the analytical data were identical to those reported.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Purification on RP 18 3 J H,H = 7.0 Hz, CH 3 -alkyl). 13 C NMR (151 MHz, CD 3 OD): δ [ppm] = 173.5 (C q -1‴), 166.4 (C q -4), 152.5 (C q -2), 152.4 (C q -4″), 137.9 (C-6), 135.1 (d, 3 J C,P = 7.6 Hz, C q -1″), 130.4 (C-2″), 130.3 (C-2″), 122.9 (2× C-3″), 112.4 (C q -5), 96.…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

“…Recently, we have shown that γ-modified nucleoside triphosphates provide such unique properties. We have studied γ-alkylketobenzyl- or long, lipophilic γ-alkyl- or γ-alkylphosphonate-modifications and observed that HIV-RT and the human DNA polymerases α, β, and γ strongly discriminate between such compounds in primer extension assays. − We report here on the synthesis, the biophysical properties, the antiviral activity, and results of primer extension assays using γ-hexadecyl-FLTTP 3 as well as its γ-acyloxybenzyl (AB)-prodrug 4 in comparison with the bis(AB)-Tri PPP ro analogue 5 (Figure ).…”

Section: Introductionmentioning

confidence: 99%

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Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

et al. 2022

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3′-Fluoro-3′-deoxythymidine (FLT) was identified as one of the most potent inhibitors of human immunodeficiency virus (HIV) replication. However, FLT also showed severe toxicity so that it was abundant as a potential chemotherapeutic agent. Here, we describe various triphosphate prodrugs of FLT aiming for (a) a bypass of all phosphorylation steps needed to convert the nucleoside analogue into its triphosphate (TP) form, (b) an intracellular delivery of hydrolytically and enzymatically stable triphosphate derivatives, and (c) increasing the selectivity for HIV-RT vs three cellular DNA polymerases including the mitochondrial DNA polymerase γ. γ-Alkylated FLTTP compounds fulfill all of these requirements because these compounds proved highly resistant to dephosphorylation and showed strong selectivity for HIV-RT. Moreover, a prodrug form of these compounds proved to be nontoxic in CEM cells.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

et al. 2022

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Lipophilic Nucleoside Triphosphate Prodrugs of Anti‐HIV Active Nucleoside Analogs as Potential Antiviral Compounds

Jia,

Schols,

Meier

2023

Advanced Science

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Nucleoside analogs require three phosphorylation steps catalyzed by cellular kinases to give their triphosphorylated metabolites. Herein, the synthesis of two types of triphosphate prodrugs of different nucleoside analogs is disclosed. Triphosphates comprising: i) a γ‐phosphate or γ‐phosphonate bearing a bioreversible acyloxybenzyl group and a long alkyl group and ii) γ‐dialkyl phosphate/phosphonate modified nucleoside triphosphate analogs. Almost selective conversion of the former TriPPPro‐compounds into the corresponding γ‐alkylated nucleoside triphosphate derivatives is demonstrated in CEM/0 cell extracts that proved to be stable toward further hydrolysis. The latter γ‐dialkylated triphosphate derivatives lead to the slow formation of the corresponding NDPs. Both types of TriPPPro‐compounds are highly potent in wild‐type CEM/0 cells and more importantly, they exhibit even better activities against HIV‐2 replication in CEM/TK− cell cultures. A finding of major importance is that, in primer extension assays, γ‐phosphate‐modified‐NTPs, γ‐mono‐alkylated‐triphosphates, and NDPs prove to be substrates for HIV‐RT but not for cellular DNA‐polymerases α,γ.

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Potent Anti‐HIV Activity of Alkyl‐Modified DiPPro‐Nucleotides

Jia,

Schols,

Meier

2023

Small Structures

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Two convergent approaches for synthesizing a new class of nucleoside diphosphate prodrugs bearing different nucleoside analogs are reported herein. The DiPPro‐nucleotides comprise an acyloxybenzyl group in combination with a lipophilic alkyl residue at the β‐phosphate or β‐phosphonate group, respectively. They are selectively cleaved to form their corresponding β‐alkylated nucleoside diphosphate derivatives in chemical and biological hydrolysis studies. In contrast, there is a selective but slow cleavage observed in the hydrolysis of the DiPPro‐compounds bearing two different, nonbioreversible alkyl moieties in human CD4+ T‐lymphocyte CEM/0 cell extracts. In these studies, the delivery of nucleoside monophosphates rather than nucleoside diphosphates is being observed, most likely due to a pure chemical phosphoranhydride cleavage of the β‐phosph(on)ate moiety. The antiviral evaluation of these two types of prodrugs reveals that these compounds exhibit marked anti‐HIV efficacy in HIV‐2‐infected thymidine kinase‐deficient CD4+ CEM T‐cells (CEM/TK−), with significantly better activities (up to 6700‐fold) against HIV‐2 replication than the parent nucleosides. Primer extension assays demonstrate that the β‐dialkylphosphate‐modified nucleoside derivatives, β‐monoalkylated‐diphosphates, and nucleoside diphosphates serve as substrates for HIV reverse transcriptase for the viral DNA elongation.

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γ-Ketobenzyl-Modified Nucleoside Triphosphate Prodrugs as Potential Antivirals

Cited by 10 publications

References 49 publications

Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

Triphosphate Prodrugs of the Anti-HIV-Active Compound 3′-Deoxy-3′-fluorothymidine (FLT)

Lipophilic Nucleoside Triphosphate Prodrugs of Anti‐HIV Active Nucleoside Analogs as Potential Antiviral Compounds

Potent Anti‐HIV Activity of Alkyl‐Modified DiPPro‐Nucleotides

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