Conception, modélisation, synthèse et évaluation des propriétés antivirales de nouveaux analogues de nucléosides

AIX-MARSEILLE2-BU Sci.Luminy (130552106) / SudocSudocFranceF

In Vitro Suppression of K65R Reverse Transcriptase-Mediated Tenofovir- and Adefovir-5′-Diphosphate Resistance Conferred by the Boranophosphonate Derivatives▿

9-[2-(Boranophosphonomethoxy)ethyl]adenine diphosphate (BH3-PMEApp) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine diphosphate (BH3-PMPApp), described here, represent the first nucleoside phosphonates modified on their α-phosphates that act as efficient substrates for the human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT). These analogues were synthesized and evaluated for their in vitro activity against wild-type (WT), K65R, and R72A RTs. BH3-PMEApp and BH3-PMPApp exhibit the same inhibition properties as their nonborane analogues on WT RT. However, K65R RT was found hypersensitive to BH3-PMEApp and as sensitive as WT RT to BH3-PMPApp. Moreover, the presence of the borane group restores incorporation of the analogue by R72A HIV RT, the latter being nearly inactive with regular nucleotides. The BH3-mediated suppression of HIV-1 RT resistance, formerly described with nucleoside 5′-(α-p-borano)-triphosphate analogues, is thus also conserved at the phosphonate level. The present results show that an α-phosphate modification is also possible and interesting for phosphonate analogues, a result that might find application in the search for a means to control HIV RT-mediated drug resistance

Gln151 of HIV-1 reverse transcriptase acts as a steric gate towards clinically relevant acyclic phosphonate nucleotide analogues.

International audienceIn the treatment of HIV, the loose active site of the HIV-1 reverse transcriptase (RT) allows numerous nucleotide analogues to act as proviral DNA 'chain-terminators'. Acyclic nucleotide phosphonate analogues (ANPs) represent a particular class of nucleotide analogue that does not possess a ribose moiety. The structural basis for their substrate efficiency regarding viral DNA polymerases is poorly understood

Gln151 of HIV-1 reverse transcriptase acts as a steric gate towards clinically relevant acyclic phosphonate nucleotide analogues.

International audienceIn the treatment of HIV, the loose active site of the HIV-1 reverse transcriptase (RT) allows numerous nucleotide analogues to act as proviral DNA 'chain-terminators'. Acyclic nucleotide phosphonate analogues (ANPs) represent a particular class of nucleotide analogue that does not possess a ribose moiety. The structural basis for their substrate efficiency regarding viral DNA polymerases is poorly understood

Synthesis of (±) cis-substituted cyclohexenyl and cyclohexanyl nucleosides via a double Mitsunobu-type reaction

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Synthesis, in Vitro Antiviral Evaluation, and Stability Studies of Novel α-Borano-Nucleotide Analogues of 9-[2-(Phosphonomethoxy)ethyl]adenine and ( R )-9-[2-(Phosphonomethoxy)propyl]adenine

International audienceWe describe here the synthesis of 9-[2-(boranophosphonomethoxy)ethyl]adenine (6a) and (R)-9-[2-(boranophosphonomethoxy)propyl]adenine (6b), the first alpha-boranophosphonate nucleosides in which a borane (BH3) group substitutes one nonbridging oxygen atom of the alpha-phosphonate moiety. H-phosphinates 5a and 5b and alpha-boranophosphonates 6a and 6b were evaluated for their in vitro activity against human immunodeficiency virus (HIV) infected cells and against a panel of DNA or RNA viruses. Compounds 5a, 5b, 6a, and 6b exhibited no significant antiviral activity in vitro and cytotoxicity. To measure the chemical and enzymatic stabilities of the target compounds 6a and 6b, kinetic data of decomposition for derivatives 5a, 5b, 6a, 6b, and standard compounds were studied at 37 degrees C in several media. The alpha-boranophosphonates 6a and 6b were metabolized in culture medium into H-phosphinates 5a and 5b, with half-live values of 5.3 h for 6a and 1.3 h for 6b

Synthesis and antiviral activity of boranophosphonate isosteres of AZT and d4T monophosphates

We report synthesis, in vitro antiviral activity, and stability studies in biological media of original boranophosphonate isosteres of AZT and d4T monophophates. A convenient route for the synthesis of 3'-Azido-3'-deoxythymidine-5'-boranophosphonate 8 and 2',3'-Didehydro-3'-dideoxythymidine-5'-boranophosphonate 12 is described. H-phosphinates 7 and 11, and alpha-boranophosphonates 8 and 12 exhibited no significant in vitro activity against HIV-infected cells, neither against a broad panel of viruses, up to 200 microM. The absence of activity of target compounds 8 and 12 can be partially explained by their short half-life in culture medium.status: publishe

Synthesis and antiviral activity of boranophosphonate isosteres of AZT and d4T monophosphates

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