Deoxyribonucleoside 2‘- or 3‘-Mixed Disulfides:  Prodrugs To Target Ribonucleotide Reductase and/or To Inhibit HIV Reverse Transcription

• Published in: Journal of medicinal chemistry Vol. 46; no. 13; pp. 2565 - 2568
• Main Authors: Roy, Béatrice, Chambert, Stéphane, Lepoivre, Michel, Aubertin, Anne-Marie, Balzarini, Jan, Décout, Jean-Luc
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.06.2003; Amer Chemical Soc
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antineoplastic agents; Antiviral agents; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; Chemistry, Medicinal; Deoxyribonucleosides - chemical synthesis; Deoxyribonucleosides - chemistry; Deoxyribonucleosides - pharmacology; Disulfides - chemical synthesis; Disulfides - chemistry; Disulfides - pharmacology; General aspects; HIV-1 - drug effects; HIV-2 - drug effects; Humans; Life Sciences & Biomedicine; Medical sciences; Mice; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Prodrugs - chemical synthesis; Prodrugs - chemistry; Prodrugs - pharmacology; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Ribonucleotide Reductases - antagonists & inhibitors; Science & Technology; Stavudine - analogs & derivatives; Stavudine - chemical synthesis; Stavudine - chemistry; Stavudine - pharmacology; Structure-Activity Relationship; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; HYDROXYUREA; PYRIMIDINE; DNA-SYNTHESIS; NUCLEOSIDE CHEMISTRY; DERIVATIVES; BIOLOGICAL APPLICATIONS; SUGAR; Antineoplastic agent; RNA-directed DNA polymerase; Cytotoxicity; L1210-Leukemia; Deoxyribonucleoside; Organic disulfide; Structure activity relation; Antiviral; Mammary gland; Acute lymphocytic leukemia; Mechanism of action; Ribonucleoside-diphosphate reductase; Chemical synthesis; Pyrimidine nucleoside; Tumor cell; Human; Enzyme; Transferases; Rodentia; Retroviridae; Enzyme inhibitor; Prodrug; Lentivirus; In vitro; Virus; Nucleotidyltransferases; Vertebrata; Mammalia; Cell line; Mouse; Dideoxynucleoside; Oxidoreductases; Human immunodeficiency virus
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm0256225

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.