title: Highly potent and selective inhibition of human immunodeficiency virus type 1 by a novel series of 6-substituted acyclouridine derivatives.
abstract: In the search for novel derivatives of 1-[2-(hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT), we have found that several 5-ethyl-6-(3,5-dimethylphenylthio)uracil and 5-ethyl-6-(3,5-dimethylbenzyl)uracil analogues are exquisitely potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in a variety of cell culture systems. Of this series, 5-ethyl-1-ethoxymethyl-6-(3,5-dimethylbenzyl)uracil (E-EBU-dM) emerged as the most active congener. Its 50% inhibitory concentration for HIV-1 (HTLV-IIIB) in MT-4 cells and peripheral blood lymphocytes is 2.2 and 0.45 nM, respectively. These concentrations are more than 10(5)-fold lower than the 50% cytotoxic concentrations of E-EBU-dM for the host cells. All compounds proved equally inhibitory to a number of clinical HIV-1 isolates, including a 3'-azido-2',3'-dideoxythymidine-resistant variant. However, as previously noted for HEPT, they do not inhibit human immunodeficiency virus type 2 replication. Reverse transcriptase assays have revealed that these HEPT derivatives act specifically on HIV-1 reverse transcriptase, according to a mechanism that is different from that of the dideoxynucleosides.
authors.affiliation: Department of Bacteriology, Fukushima Medical College, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: E
authors.initials: E
authors.lastname: De Clercq
authors.forename: H
authors.initials: H
authors.lastname: Tanaka
authors.forename: M
authors.initials: M
authors.lastname: Ubasawa
authors.forename: H
authors.initials: H
authors.lastname: Takashima
authors.forename: K
authors.initials: K
authors.lastname: Sekiya
authors.forename: I
authors.initials: I
authors.lastname: Nitta
authors.forename: K
authors.initials: K
authors.lastname: Umezu
authors.forename: R T
authors.initials: RT
authors.lastname: Walker
authors.forename: S
authors.initials: S
authors.lastname: Mori
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship; D013941:Thymine / Q000031:analogs & derivatives* / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
chemical_list: D000998:Antiviral Agents; D018894:Reverse Transcriptase Inhibitors; C061818:1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine; D015215:Zidovudine; D013941:Thymine