title: 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.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja s/n, 18071 Granada, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Gómez-Pérez
authors.forename: Theresa
authors.initials: T
authors.lastname: McSorley
authors.forename: Wei Cun
authors.initials: WC
authors.lastname: See Too
authors.forename: Manfred
authors.initials: M
authors.lastname: Konrad
authors.forename: Joaquín M
authors.initials: JM
authors.lastname: Campos
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D005260:Female; D006801:Humans; D007700:Kinetics; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011806:Quinolinium Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011726:Pyridinium Compounds; D011806:Quinolinium Compounds; C517212:CHKA protein, human; D002797:Choline Kinase