Synthesis of 2′,3′,5′-trideoxyuridine-5′-methylphosphonic Acid and its Diphosphate Derivative. Study of the Interaction with HIV-1 reverse Transcriptase

Benzaria, S.; Maury, Georges; Gosselin, Gilles; Rittinger, Katrin; Divita, Gilles; Goody, Roger S.; Imbach, J.‐L.

doi:10.1177/095632029400500403

Cited by 2 publications

(2 citation statements)

References 25 publications

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“…Isosteric substitution of the 5‘-oxygen by methylene for AZTTP reduces the catalytic efficiency of HIV-RT by 1800-fold. The same substitution for ddUTP makes it a very poor substrate of HIV-RT …”

Section: Discussionmentioning

confidence: 99%

“…The same substitution for ddUTP makes it a very poor substrate of HIV-RT. 30 The failure of three other phosphono diphosphates, 1a, 4a, and 5a, to be accepted as a substrate by NS5B RdRp highlights the other key structural features required by a nucleotide chain terminator. A structural comparison of 1a to 2a, 3a to 4a, and 2a to 5a respectively suggests that shortening spacing between the 5′-carbon to phosphorus, replacement of the ribose bridge oxygen by a carbon, or addition of a 2′-methyl group is detrimental for a phosphonate to function as a chain terminator.…”

Section: Discussionmentioning

confidence: 99%

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Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

Koh

Shim

et al. 2005

J. Med. Chem.

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A series of adenosine 5′-phosphonate analogues were designed to mimic naturally occurring adenosine monophosphate. These compounds (1-5) were synthesized and evaluated in a cellular hepatitis C virus (HCV) replication assay. To improve cellular permeability and enhance the anti-HCV activity of these phosphonates, a bis(S-acyl-2-thioethyl) prodrug for compound 5 was prepared, and its cellular activity was determined. To elucidate the mechanism of action of these novel adenosine phosphonates, their diphosphate derivatives (1a-5a) were synthesized. Further nucleotide incorporation assays by HCV NS5B RNA-dependent RNA polymerase revealed that 2a and 3a can serve as chain terminators, whereas compounds 1a, 4a, and 5a are competitive inhibitors with ATP. Additional steady-state kinetic analysis determined the incorporation efficiency of 2a and 3a as well as the inhibition constants for 1a, 4a, and 5a. The structure-activity relationships among these compounds were analyzed, and the implication for nucleoside phosphonate drug design was discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

Koh

Shim

et al. 2005

J. Med. Chem.

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Pyrophosphoryl Derivatives of 1-(2-Deoxy-3-O-Phosphonomethyl-β-and-α-D-Erythro-Pentofuranosyl)Thymine: Synthesis and Substrate Properties Towards Some DNA Polymerases

Mikhailopulo

Кулак

Ткаченко

et al. 2000

Nucleosides, Nucleotides and Nucleic Acids

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The synthesis of 1-(2-deoxy-3-O-phosphonomethyl-beta-D-erythropentofuranosyl)thymine (17) and its alpha-anomer 18 is described. Attempts to prepare 1-[2-deoxy-3-O-(pyrophosphoryl)phosphonomethyl-beta-D-erythro-pentofuranosyl]thymine (19) by an activation of the respective phosphonate 17 with 1,1'-carbonyldiimidazole (Im2CO) resulted in the quantitative formation of the corresponding pyrophosphonate derivative 21 (Scheme 2). Activation of inorganic pyrophosphate with Im2CO followed by the condensation with the phosphonates 17 and 18 afforded the desired analogues of nucleoside triphosphate 19 (35%) and its alpha-anomer 20 (27%) along with the respective pyrophosphonate derivatives 21 (37%) and 24 (38%) (Scheme 3). It was found that compounds 19 and 20 display (i) no substrate properties toward calf thymus terminal deoxynucleotidyl transferase (TDT) and AMV reverse transcriptase, and (ii) moderate substrate activity with E. coli DNA polymerase I (Klenow fragment).

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Synthesis of 2′,3′,5′-trideoxyuridine-5′-methylphosphonic Acid and its Diphosphate Derivative. Study of the Interaction with HIV-1 reverse Transcriptase

Cited by 2 publications

References 25 publications

Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

Design, Synthesis, and Antiviral Activity of Adenosine 5‘-Phosphonate Analogues as Chain Terminators against Hepatitis C Virus

Pyrophosphoryl Derivatives of 1-(2-Deoxy-3-O-Phosphonomethyl-β-and-α-D-Erythro-Pentofuranosyl)Thymine: Synthesis and Substrate Properties Towards Some DNA Polymerases

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