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Novel 4-Amino Bis-pyridinium and Bis-quinolinium Derivatives as Choline Kinase Inhibitors with Antiproliferative Activity against the Human Breast Cancer SKBR-3 Cell Line

Authors

  • Verónica Gómez-Pérez,

    1. Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada (Spain)
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  • Dr. Theresa McSorley,

    1. Enzyme Biochemistry Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen (Germany)
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  • Dr. Wei Cun See Too,

    1. Enzyme Biochemistry Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen (Germany)
    2. Current address: School of Health Sciences, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan (Malaysia)
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  • Dr. Manfred Konrad,

    1. Enzyme Biochemistry Group, Max Planck Institute for Biophysical Chemistry, 37077 Göttingen (Germany)
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  • Dr. Joaquín M. Campos

    Corresponding author
    1. Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada (Spain)
    • Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada (Spain)
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Abstract

Choline kinase (ChoK) is the first enzyme in the CDP-choline pathway that synthesizes phosphatidylcholine, the major phospholipid in eukaryotic cell membranes. Human ChoK has three isoforms: ChoKα1, α2, and β. Specific inhibition of ChoKα has been reported to selectively kill tumor cells. In this study, ten new symmetrical bis-pyridinium and bis-quinolinium derivatives were synthesized and tested for their ability to inhibit human ChoKα2. These compounds have electron-releasing groups at position 4 of the pyridinium or quinolinium rings. 1,1′-[(Butane-1,3-diylbis(benzene-1,4-diylmethylene)]bis[4-(4-bromo-N-methylanilino)pyridinium)] dibromide and 1,1′-(biphenyl-3,3′-diylmethylene)bis[7-chloro-4-(perhydroazepine-1-yl)quinolinium] dibromide were identified as highly potent ChoK inhibitors with IC50 values of 80 nM. Kinetic enzymatic assays indicated a mixed and predominantly competitive mechanism of inhibition for these compounds, which exhibited strong antiproliferative activity (EC50 1 μM) against the human breast cancer SKBR3 cell line.

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