title: Potent and selective inhibition of human immunodeficiency virus type 1 transcription by piperazinyloxoquinoline derivatives.
abstract: We have found novel piperazinyloxoquinoline derivatives to be potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) replication in both acutely and chronically infected cells. 8-Difluoromethoxy-1-ethyl-6-fluoro-1,4-didehydro-7-[4-(2-met hoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12), the most potent congener of the series, completely inhibited HIV-1 replication in acutely infected MOLT-4 cells at a concentration of 0.16 to 0.8 microM without showing any cytotoxicity. The compound completely suppressed tumor necrosis factor alpha (TNF-alpha)-induced HIV-1 expression in latently infected cells (OM-10.1) and constitutive viral production in chronically infected cells (MOLT-4/III(B)) at a concentration of 0.8 microM. K-12 could also inhibit HIV-1 antigen expression in OM-10.1 and MOLT-4/III(B) cells at this concentration. Northern blot analysis revealed that K-12 selectively prevented the accumulation of HIV-1 mRNA in MOLT-4/III(B) and TNF-alpha-treated OM-10.1 cells in a dose-dependent fashion. It was not inhibitory to HIV-1 Tat or the cellular transcription factors NF-kappaB and Sp1, suggesting that the piperazinyloxoquinoline derivatives are a group of HIV-1 transcription inhibitors with a unique mechanism of action.
authors.affiliation: Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Sakuragaoka, Japan. baba@med3.kufm.kagoshima-u.ac.jp
authors.forename: M
authors.initials: M
authors.lastname: Baba
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: M
authors.initials: M
authors.lastname: Makino
authors.forename: Y
authors.initials: Y
authors.lastname: Kimura
authors.forename: T
authors.initials: T
authors.lastname: Ikeuchi
authors.forename: T
authors.initials: T
authors.lastname: Sakaguchi
authors.forename: T
authors.initials: T
authors.lastname: Okamoto
mesh_terms: D019380:Anti-HIV Agents / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000821:virology; D002478:Cells, Cultured; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D010879:Piperazines / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D010879:Piperazines; D011804:Quinolines