title: Anti-retrovirus activity of 3'-fluoro- and 3'-azido-substituted pyrimidine 2',3'-dideoxynucleoside analogues.
abstract: The 3'-fluoro-and 3'-azido-substituted derivatives of 2',3'-dideoxythymidine (ddThd), 2',3'-dideoxyuridine (ddUrd), 2',3'-dideoxy-5-ethyluridine (ddEtUrd) and 2',3'-dideoxycytidine (ddCyd) have been synthesized and evaluated for their anti-retrovirus activity [against human immunodeficiency virus (HIV) and murine Moloney sarcoma virus (MSV)]. Based on their 50% effective doses the most potent inhibitors of HIV replication in human MT4 lymphocytes were: FddThd (0.001 microM), AzddThd (0.004 microM), FddUrd (0.04 microM) and AzddUrd (0.36 microM). Their selectivity indexes were 197, 5000, 500 and 677, respectively. In contrast, none of the 3'-substituted ddEtUrd derivatives had a marked antiviral effect. The 2',3'-dideoxynucleoside analogues showed poor, if any, substrate affinity for (bacterial) dThd phosphorylase. AzddThd and FddThd inhibited human dThd kinase to a much greater extent (Ki/Km: 0.66 and 3.4, respectively) than did AzddUrd or FddUrd (Ki/Km: 71 and 171, respectively). The Ki/Km values of FddCyd and AzddCyd for human dCyd kinase were about 60. Although phosphorylation is a prerequisite for the anti-retrovirus activity of the 2',3'-dideoxynucleoside derivatives, there is no close correlation between the anti-retrovirus potency of the 3'-fluoro- and 3'-azido-substituted ddUrd, ddThd, ddEtUrd and ddCyd derivatives and their affinity for dThd kinase or dCyd kinase.
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: P
authors.initials: P
authors.lastname: Herdewijn
authors.forename: E
authors.initials: E
authors.lastname: De Clerq
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000096:biosynthesis; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D003842:Deoxycytidine Kinase / Q000378:metabolism; D015224:Dideoxynucleosides; D006678:HIV / Q000187:drug effects; D007700:Kinetics; D051379:Mice; D010766:Phosphorylation; D011741:Pyrimidine Nucleosides / Q000494:pharmacology*; D012190:Retroviridae / Q000187:drug effects*; D013936:Thymidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013937:Thymidine Kinase / Q000378:metabolism; D016047:Zalcitabine
chemical_list: D000963:Antimetabolites; D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011741:Pyrimidine Nucleosides; D003841:Deoxycytidine; C019336:2',3'-dideoxythymidine; D016047:Zalcitabine; D004247:DNA; D013937:Thymidine Kinase; D003842:Deoxycytidine Kinase; D013936:Thymidine