Deoxyribonucleoside 2'- or 3'-mixed disulfides: prodrugs to target ribonucleotide reductase and/or to inhibit HIV reverse transcription.
Herein, we report the design, synthesis, and biological effects of nucleosides bearing a disulfide function on the sugar ring as prodrugs of potentially active mercaptonucleotides that can target ribonucleotide reductase or reverse transcriptase. We show that cytidine derivatives efficiently reduce dNTP pools in human CEM/SS cells and that 3'-deoxythymidin-3'-yl methyl disulfide is able to interfere with both cellular dNTP synthesis and HIV reverse transcription.
Roy
Béatrice
B
Institut de Biochimie Biophysique Moléculaire et Cellulaire, UMR 8619 CNRS, Université de Paris Sud, F-91405 Orsay, France. beatrice.roy@bbmpc.u-psud.fr
Chambert
Stéphane
S
Lepoivre
Michel
M
Aubertin
Anne-Marie
AM
Balzarini
Jan
J
Décout
Jean-Luc
JL
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003853:Deoxyribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004220:Disulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors*; D018119:Stavudine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects
C475512:3'-deoxythymidin-3'-yl methyl disulfide; D019380:Anti-HIV Agents; D003853:Deoxyribonucleosides; D004220:Disulfides; D011355:Prodrugs; D018894:Reverse Transcriptase Inhibitors; D018119:Stavudine; D012264:Ribonucleotide Reductases