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Research ArticleArticle

Inhibition of Human Immunodeficiency Virus Type 1 Replication and Cytokine Production by Fluoroquinoline Derivatives

Masanori Baba, Mika Okamoto, Masaki Kawamura, Masahiko Makino, Tomoe Higashida, Tohru Takashi, Youichi Kimura, Tohru Ikeuchi, Toshifumi Tetsuka and Takashi Okamoto
Molecular Pharmacology June 1998, 53 (6) 1097-1103;
Masanori Baba
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Mika Okamoto
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Masaki Kawamura
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Masahiko Makino
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Tomoe Higashida
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Tohru Takashi
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Youichi Kimura
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Tohru Ikeuchi
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Toshifumi Tetsuka
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Takashi Okamoto
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Abstract

We have recently identified 8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12) as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In the search for more effective derivatives and their mode of action, we have found 7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carboxylic acid (K-37) and 8-difluoromethoxy-1,4-dihydro-6-fluoro-7-(3,4-dehydro-4-phenyl-1-piperidinyl)1-[4,(1,2,4-triazol-1-yl)methylphenyl]-4-oxoquinoline-3-carboxylic acid (K-38) to be more potent inhibitors of HIV-1 replication than K-12. The EC50 values of K-37 and K-38 for HIV-1IIIB were 27 and 3.8 nm in peripheral blood mononuclear cells, respectively. These values were approximately 3- and 24-fold lower than the EC50 of K-12. K-38 was also a more potent inhibitor of HIV-1 replication in chronically infected cells, such as tumor necrosis factor α-stimulated OM-10.1 cells. K-37 and K-38 proved to be more cytotoxic than K-12 for a variety of cell lines as well as peripheral blood mononuclear cells. These compounds were more inhibitory of Tat-induced HIV-1 long terminal repeat-driven gene expression than K-12, which suggests that their mechanism of action is attributable in part to the inhibition of Tat function. Interestingly, K-37 and K-38 could suppress the production of tumor necrosis factor α and interleukin 6 in phytohemagglutinin-stimulated peripheral blood mononuclear cells and the expression of intercellular adhesion molecule 1 in tumor necrosis factor α-stimulated human umbilical vein endothelial cells at their nontoxic concentrations. In contrast, another K-12 derivative, 1,4-dihydro-8-dimethylaminomethyl-6-fluoro-7-[4-(2-methoxyphenyl)-1-piperadinyl]-1-methyl-4-oxoquinoline-3-carboxylic acid (K-42), had anti-HIV-1 activity and cytotoxicity profiles similar to those of K-12, but K-42 scarcely inhibited the cytokine production and intercellular adhesion molecule 1 expression.

Footnotes

  • Send reprint requests to: Dr. Masanori Baba, Division of Human Retroviruses, Ctr for Chronic Viral Disease, Faculty of Medicine, Kagoshima University, 8–35-1, Sakuragaoka, Kagoshima 890, Japan. E-mail: baba{at}med3.kufm.kagoshima-u.ac.jp

  • This work was supported in part by the Japan Health Science Foundation.

  • Abbreviations:
    HIV-1
    human immunodeficiency virus type 1
    NF
    nuclear factor
    TNF-α
    tumor necrosis factor α
    LTR
    long terminal repeat
    NAC
    N-acetyl-l-cysteine
    K-12
    8-difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carboxylic acid
    IL
    interleukin
    ICAM
    intercellular adhesion molecule
    K-37
    7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1,4-dihydro-6-fluoro-1-methyl-8-trifluoromethyl-4-oxoquinoline-3-carboxylic acid
    K-38
    8-difluoromethoxy-1,4-dihydro-6-fluoro-7-(3,4-dehydro-4-phenyl-1-piperidinyl)-1-[4,(1,2,4-triazol-1-yl)methylphenyl]-4-oxoquinoline-3-carboxylic acid
    K-42
    1,4-dihydro-8-dimethylaminomethyl-6-fluoro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-1-methyl-4-oxoquinoline-3-carboxylic acid
    BTC
    5-methoxy-3-(1-methylethoxy)-benzo[b]thiophene-2-carboxamide
    PBMC
    peripheral blood mononuclear cell
    PHA
    phytohemagglutinin
    HUVEC
    human umbilical vein endothelial cell
    MTT
    3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
    CAT
    chloramphenicol acetyltransferase
    SI
    selectivity index
    HTLV-I
    human T-lymphotropic virus type I
    • Received December 29, 1997.
    • Accepted February 13, 1998.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 53 (6)
Molecular Pharmacology
Vol. 53, Issue 6
1 Jun 1998
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Research ArticleArticle

Inhibition of Human Immunodeficiency Virus Type 1 Replication and Cytokine Production by Fluoroquinoline Derivatives

Masanori Baba, Mika Okamoto, Masaki Kawamura, Masahiko Makino, Tomoe Higashida, Tohru Takashi, Youichi Kimura, Tohru Ikeuchi, Toshifumi Tetsuka and Takashi Okamoto
Molecular Pharmacology June 1, 1998, 53 (6) 1097-1103;

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Research ArticleArticle

Inhibition of Human Immunodeficiency Virus Type 1 Replication and Cytokine Production by Fluoroquinoline Derivatives

Masanori Baba, Mika Okamoto, Masaki Kawamura, Masahiko Makino, Tomoe Higashida, Tohru Takashi, Youichi Kimura, Tohru Ikeuchi, Toshifumi Tetsuka and Takashi Okamoto
Molecular Pharmacology June 1, 1998, 53 (6) 1097-1103;
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