title: 5-Halogeno-3'-fluoro-2',3'-dideoxyuridines as inhibitors of human immunodeficiency virus (HIV): potent and selective anti-HIV activity of 3'-fluoro-2',3'-dideoxy-5-chlorouridine.
abstract: The novel 5-chloro-, 5-bromo-, and 5-iodo-derivatives of 3'-fluoro-2',3'-dideoxyuridine (FddUrd), designated FddCIUrd, FddBrUrd, and FddIUrd, respectively, have been synthesized and evaluated for their antiretrovirus activity against human immunodeficiency virus (HIV) and murine Moloney sarcoma virus. All three 5-halogeno-FddUrd analogues inhibited HIV-1 replication in MT4 cells with an effective dose (ED50) of about 0.2-0.4 microM. However, FddCIUrd was markedly more selective in its anti-HIV-1 activity than FddBrUrd or FddIUrd. The selectivity index of FddCIUrd was similar to that of 3'-azido-2',3'-dideoxythymidine (AZT) when evaluated in parallel (1408 and 1603, respectively). The FddUrd derivatives also had a marked inhibitory effect on HIV-2 replication in MT4 cells and HIV-1 induced antigen expression in HUT-78 cells. However, neither FddUrd nor its 5-halogeno derivatives were inhibitory to Moloney sarcoma virus-induced transformation of murine C3H cells. The anti-HIV-1 activity of FddUrd, FddCIUrd, FddBrUrd, and FddIUrd was reversed by the addition of thymidine and 2'-deoxycytidine. The 5-halogeno-FddUrd analogues had a markedly higher affinity for MT4 thymidine kinase than FddUrd (Ki/Km, 4.0-4.7, as compared with 302 for FddUrd).
authors.affiliation: Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
authors.forename: J
authors.initials: J
authors.lastname: Balzarini
authors.forename: A
authors.initials: A
authors.lastname: Van Aerschot
authors.forename: R
authors.initials: R
authors.lastname: Pauwels
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: D
authors.initials: D
authors.lastname: Schols
authors.forename: P
authors.initials: P
authors.lastname: Herdewijn
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002472:Cell Transformation, Viral / Q000187:drug effects; D003841:Deoxycytidine / Q000494:pharmacology; D015224:Dideoxynucleosides / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects*; D006219:Halogens; D010766:Phosphorylation; D013936:Thymidine / Q000494:pharmacology; D014529:Uridine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D015224:Dideoxynucleosides; D006219:Halogens; D003841:Deoxycytidine; C059695:3'-fluoro-2',3'-dideoxy-5-bromouridine; C059694:raluridine; C059696:3'-fluoro-2',3'-dideoxy-5-iodouridine; C058924:3'-fluoro-2',3'-dideoxyuridine; D013936:Thymidine; D014529:Uridine