title: Acridone derivatives are selective inhibitors of HIV-1 replication in chronically infected cells.
abstract: In our extensive screening of anti-HIV-1 agents in chronically infected cell lines, we have found acridone derivatives to be selective inhibitors of HIV-1 replication. Among the acridone derivatives, 1-hydroxy-10-methyl-9,10-dihydroacrid-9-one (RD6-5071) suppressed tumor necrosis factor (TNF)-alpha-induced HIV-1 expression in the latently infected cell line OM-10.1, U1, and ACH-2. Its 50% effective concentration for HIV-1 p24 antigen production was 2.0 microg/ml in OM-10.1 cells, while its 50% cytotoxic concentration was 18 microg/ml. The compound also inhibited phorbol 12-myristate 13-acetate (PMA)-induced HIV-1 expression in these cell lines. Furthermore, RD6-5071 was inhibitory to HIV-1 replication in acutely infected U937 and peripheral blood mononuclear cells. The compound was found to suppress TNF-alpha-induced HIV-1 long terminal repeat-driven gene expression. An inhibition assay for protein kinase C (PKC) revealed that RD6-5071 could reduce the enzyme activity. Furthermore, the compound was a moderate inhibitor of PMA-induced nuclear factor kappaB (NF-kappaB) activation, as determined by a gel mobility shift analysis. These results suggest that the acridone derivatives suppress HIV-1 replication at the transcriptional level primarily through a mechanism of PKC inhibition.
authors.affiliation: Rational Drug Design Laboratories, Fukushima, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fujiwara
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: M
authors.initials: M
authors.lastname: Okamoto
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.forename: H
authors.initials: H
authors.lastname: Machida
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: T
authors.initials: T
authors.lastname: Yokota
authors.forename: M
authors.initials: M
authors.lastname: Baba
mesh_terms: D000166:Acridines / Q000737:chemistry / Q000494:pharmacology*; D054831:Acridones; D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D005434:Flow Cytometry; D015497:HIV-1 / Q000187:drug effects*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000166:Acridines; D054831:Acridones; D019380:Anti-HIV Agents; D004791:Enzyme Inhibitors; C402748:RD6 5071; D014409:Tumor Necrosis Factor-alpha; C041300:acridone; D011493:Protein Kinase C