Inhibition of human immunodeficiency virus type 1 replication and cytokine production by fluoroquinoline derivatives.
We have recently identified 8-difluoromethoxy-1-ethyl-6-fluoro-1, 4-dihydro-7-[4-(2-methoxyphenyl)-1-piperazinyl]-4-oxoquinoline-3-carb oxylic 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 alpha-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 alpha and interleukin 6 in phytohemagglutinin-stimulated peripheral blood mononuclear cells and the expression of intercellular adhesion molecule 1 in tumor necrosis factor alpha-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-pip eradinyl]-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.
Baba
M
M
Division of Human Retroviruses, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890, Japan. baba@med3.kufm.kagoshima-u.ac.jp
Okamoto
M
M
Kawamura
M
M
Makino
M
M
Higashida
T
T
Takashi
T
T
Kimura
Y
Y
Ikeuchi
T
T
Tetsuka
T
T
Okamoto
T
T
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis*; D015696:Gene Products, tat / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D011804:Quinolines / Q000494:pharmacology*; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D016207:Cytokines; D015696:Gene Products, tat; D011804:Quinolines; D054322:tat Gene Products, Human Immunodeficiency Virus; D018799:Intercellular Adhesion Molecule-1