Anti-retroviral and cytostatic activity of 2',3'-dideoxyribonucleoside 3'-disulfides.
Herein, we report the synthesis, antiviral and cytostatic effects of nucleosides bearing a 3'-disulfide function as prodrugs of potentially active 3'-mercaptonucleotides. The lack of the anti-HIV effects in mutant CEM/TK-cells for most of the thymidine disulfides suggests that a phosphorylation step involving thymidine kinase is necessary for the eventual antiviral activity of the thymidine nucleosides. The comparable anti-HIV activities of most of the disulfides and their rapid reduction in CEM cell extracts imply an inhibitory effect of the 2',3'-dideoxy-3'-mercaptothymidine 5'-triphosphate metabolite. The cytostatic effects of the disulfides in CEM/0 and Molt4/C8 cells appeared to be strongly dependent on the nature of the non-nucleosidic disulfide moiety and were decreased in preserving the anti-retroviral activity.
Gerland
Béatrice
B
Université de Grenoble/CNRS, UMR 5063, Département de Pharmacochimie Moléculaire, ICMG FR 2607, BP 53 F-38041 Grenoble Cedex 9, France.
Désiré
Jérôme
J
Balzarini
Jan
J
Décout
Jean-Luc
JL
D019380:Anti-HIV Agents / Q000737:chemistry; D044966:Anti-Retroviral Agents / Q000737:chemistry*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D015224:Dideoxynucleosides / Q000737:chemistry / Q000494:pharmacology*; D004220:Disulfides / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010766:Phosphorylation; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000378:metabolism
D019380:Anti-HIV Agents; D044966:Anti-Retroviral Agents; D015224:Dideoxynucleosides; D004220:Disulfides; D013937:Thymidine Kinase