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.

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 IC(50) values of 80 nM. Kinetic enzymatic assays indicated a mixed and predominantly competitive mechanism of inhibition for these compounds, which exhibited strong antiproliferative activity (EC(50) 1 μM) against the human breast cancer SKBR3 cell line.

• Authors: Verónica Gómez-Pérez, Theresa McSorley, Wei Cun See Too, Manfred Konrad, Joaquín M Campos
• Journal: ChemMedChem (ChemMedChem) Vol. 7 Issue 4 Pg. 663-9 (Apr 2012) ISSN: 1860-7187 [Electronic] Germany
• PMID: 22278967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Pyridinium Compounds
• Quinolinium Compounds
• CHKA protein, human
• Choline Kinase

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Breast Neoplasms (drug therapy, pathology)
• Cell Line, Tumor
• Choline Kinase (antagonists & inhibitors)
• Drug Screening Assays, Antitumor
• Enzyme Inhibitors (chemical synthesis, chemistry, pharmacology)
• Female
• Humans
• Kinetics
• Pyridinium Compounds (chemical synthesis, chemistry, pharmacology)
• Quinolinium Compounds (chemical synthesis, chemistry)
• Structure-Activity Relationship