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.

4-Amino Bis-Pyridinium Derivatives as Novel Antileishmanial Agents

“…The synthesis of choline kinase inhibitors has been described previously (7). The compounds tested (see Table S1 in the supplemental material) were dissolved in dimethyl sulfoxide (DMSO) at 10 mM.…”

“…We previously designed and synthesized a new set of bis-pyridinium compounds as inhibitors of the human choline kinase enzyme (7). This enzyme is a validated antitumor target, and all the above-mentioned compounds have shown a significant antiproliferative activity (7).…”

“…This enzyme is a validated antitumor target, and all the above-mentioned compounds have shown a significant antiproliferative activity (7). Additionally, these compounds can be considered structural analogues of pentamidine in which the amidine moieties, which are protonated at physiological pH, have been replaced by positively charged nitrogen atoms in a pyridinium ring.…”

Design, synthesis and anti-leishmanial activity of novel symmetrical bispyridinium cyclophanes

“…This enzyme is a validated anti-tumor target and all the abovementioned compounds have shown a significant antiproliferative activity [9]. These compounds can be considered as structural analogues of pentamidine in which the amidino moiety, which is protonated at physiological pH, has been replaced by a positively charged nitrogen atom as a pyridinium ring.…”

3D-QSAR and Molecular Docking Studies on Benzotriazoles as Antiproliferative Agents and Histone Deacetylase Inhibitors

“…1 Recently, many classes of compounds showed antiproliferative activity against human cancer cells including dihydro-1,3,5-triazines, 2 bis-quinolinium derivatives, 3 4-aminomethylidene derivatives, 4 aroylacrylic acids, 5 etc. were synthesized and several compounds showed promising inhibitory potency in clinical trials.…”