Design, synthesis, theoretical calculations and biological evaluation of new non-symmetrical choline kinase inhibitors

Inhibition of Choline Kinase (ChoK) has been reported as a therapeutical target in the treatment of some kinds of tumor. In this paper, the design and synthesis of new non-symmetrical monocationic ChoK inhibitors is described, bearing a cationic head and an adenine moiety connected by linkers of different lengths. Docking studies indicate that the cationic head of these compounds could be inserted into the choline binding site of the enzyme, while the adenine moiety could be stabilized into the ATP binding site. Docking studies also support the difference of activity of the synthesized compounds, which depends on both the substituent at position 4 of the cationic head and the linker length, being dimethylamine and 1,4-diphenylbutane respectively, the most appropriate ones. Compounds 14 (IC50 = 10.70 ± 0.40 μM) and 17 (IC50 = 6.21 ± 0.97 μM) are the most potent ChoK inhibitors and suitable for further modification with a view to obtain more potent antitumor compounds.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► We have designed and prepared new non-symmetrical choline kinase inhibitors. ► These inhibitors bear a cationic head linked to an N-3 or N-9 adenine moiety. ► Compound 14 (IC50 = 10.70 ± 0.40 μM) is the most potent of the N-9 series. ► Compound 17 (IC50 = 6.21 ± 0.97 μM) is the most potent of the N-3 series. ► Docking studies show that could bind simultaneously in both ATP and Cho binding sites.