Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process

Puech, Frédéric; Gosselin, Gilles; Lefèbvre, Isabelle; Pompon, A.; Aubertin, Anne Marie; Kirn, A.; Imbach, J.‐L.

doi:10.1016/0166-3542(93)90093-x

Cited by 92 publications

(77 citation statements)

References 24 publications

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“…The synthesis of L-DDC and L-FDDC, which were stereospecifically obtained from L-xylose by a multistep reaction sequence, has been reported elsewhere (12 Assays in MT-4 cells. Replication of HIV-1 in MT-4 cells was determined by measuring the reduction in the viabilities of the cells resulting from the infection and was quantitated as described previously (10,11,25,27) by a colorimetric reaction based on the capacity of the cells to reduce 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) to formazan. The assays were performed in triplicate.…”

Section: Matermils and Methodsmentioning

confidence: 99%

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Gosselin

Schinazi

Sommadossi

et al. 1994

Antimicrob Agents Chemother

131

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The L enantiomer of 2',3'-dideoxycytidine (DDC) was recently shown to inhibit selectively human immunodeficiency virus type 1 (HIV-1) in vitro. In the current study, the potent anti-HIV activity of L-DDC was confirmed and extended to several HIV-1 and HIV-2 strains in various cell culture systems, including primary human lymphocytes and macrophages. Furthermore, its 5-fluoro congener, beta-L-2',3'-dideoxy-5-fluorocytidine (L-FDDC), was found to have more potent anti-HIV activity and a higher therapeutic index in acutely infected human peripheral blood mononuclear cells. These compounds had no marked activity against HIV-1 isolates resistant to the oxathiolane pyrimidine nucleosides (-)-beta-L-2',3'-dideoxy-5-fluoro-3'-thiacytidine [(-)-FTC] and (-)-beta-L-2',3'-dideoxy-3'-thiacytidine, but 3'-azido-3'-deoxythymidine (AZT)-resistant viruses were susceptible to L-DDC and L-FDDC. Cytotoxicity studies with human myeloid progenitor cells indicated that L-DDC and L-FDDC had median inhibitory concentrations comparable to those of AZT, DDC, and FDDC, but L-DDC and L-FDDC were significantly less toxic than AZT, DDC, and FDDC when erythroid progenitor cells were used. L-FDDC had the highest selectivity indices (6,000 and 9,000 for erythroid and myeloid progenitor cells, respectively) of all the compounds evaluated. Further preclinical development of L-FDDC is warranted in order to determine its potential usefulness in the treatment of HIV infections.

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Section: Matermils and Methodsmentioning

confidence: 99%

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Gosselin

Schinazi

Sommadossi

et al. 1994

Antimicrob Agents Chemother

131

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“…The synthesis of the mononucleoside phosphotriester derivatives 1-5 has been reported elsewhere (Periqaud et al, 1993;Puech et al, 1993;Lefebvre et aI., 1995). These compounds were characterized on the basis of their spectroscopic properties (UV, high-field multinuclearmagnetic resonance, fast atom bombardment mass, and rigorous high-pressure liquid chromatography) and data were consistentwith their structures and purities.…”

Section: Compoundsmentioning

confidence: 99%

“…1. ) which incorporate the MeSATE and OTE bloreversible groups, respectively (Perlqaud et al, 1993;Puech et al, 1993). Herein, the anti-HIV activity of the phosphotrlester derivatives 4 and 5 has been evaluated in human PBMCs and their selectivity was investigated by studying their effects on human bone marrow cells.…”

Section: Introductionmentioning

confidence: 99%

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Philouze

Girardet

Lefèbvre

et al. 1996

Antivir Chem Chemother

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SummaryThe effects of three mononucleoside phosphotriester derivatives of 3'-azido-2',3'-dideoxythymidine (AZT) which incorporate biolabile phosphate protecting groups, namely 5-acetyl-2-thioethyl (MeSATE), 5-(2-hydroxyethylsulfidyl)-2-thioethyl (OTE), and pivaloyloxymethyl (POM) were studied and compared to their nucleoside parent in human myeloid colony-forming cells. Moreover, the relative antiviral potency of these three pronucleotldes were determined in primary human peripheral blood mononuclear cells infected with human immunodeficiency virus type 1. The results indicate that the SATE and OTE pro-moieties, as well as their degradation products, do not induce additional toxicity. The bis(MeSATE) phosphotriester derivative of AZT emerged as the most selective inhibitor with an in-vitro therapeutic index of the same order of magnitude as observed for AZT. This study has been extended to the corresponding bis(MeSATE) and bis(OTE) phosphotriester derivatives of 2',3'-dideoxyuridine (ddU).

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“…5,6 Another approach to bypass the first phosphorylation step more completely is through phosphonate analogs, that, after intracellular conversion to their diphosphate forms, can serve as inhibitors/ chain terminators in the HIV RT reaction. [7][8][9][10] A unique feature common to all nucleoside phosphonates is their prolonged antiviral action.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of the 5'-C-phosphonate of 4(S)-(6-amino-9H-purin-9-yl) tetrahydro-2(S)-furanmethanol [S,S-IsoddA]

Nair¹,

Sharma²

2003

Arkivoc

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4(S)-(6-Amino-9H-purin-9-yl)tetrahydrofuran-2(S)-ylmethyl phosphonic acid, a 5′-Cphosphonate analog of the potent anti-HIV compound S,S-IsoddA, was synthesized in order to bypass the critical initial intracellular phosphorylation. Key phases in this multistep synthesis were the Arbuzov reaction of the 5-iodofuranose with triethylphosphite and the Mitsunobu/ coupling reaction of the phosphonate with adenine. The structure of the final product was confirmed by HRMS and multinuclear NMR data.

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Intracellular delivery of nucleoside monophosphates through a reductase-mediated activation process

Cited by 92 publications

References 24 publications

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Anti-human immunodeficiency virus activities of the beta-L enantiomer of 2',3'-dideoxycytidine and its 5-fluoro derivative in vitro

Comparison of Cytotoxicity of Mononucleoside Phosphotriester Derivatives Bearing Biolabile Phosphate Protecting Groups in Normal Human Bone Marrow Progenitor Cells

Synthesis of the 5'-C-phosphonate of 4(S)-(6-amino-9H-purin-9-yl) tetrahydro-2(S)-furanmethanol [S,S-IsoddA]

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