title: Design, synthesis, theoretical calculations and biological evaluation of new non-symmetrical choline kinase inhibitors.
abstract: 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 (IC(50) = 10.70 ± 0.40 μM) and 17 (IC(50) = 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.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Campus de Cartuja, 18071 Granada, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Rubio-Ruíz
authors.forename: Ana
authors.initials: A
authors.lastname: Conejo-García
authors.forename: Pablo
authors.initials: P
authors.lastname: Ríos-Marco
authors.forename: María Paz
authors.initials: MP
authors.lastname: Carrasco-Jiménez
authors.forename: Josefa
authors.initials: J
authors.lastname: Segovia
authors.forename: Carmen
authors.initials: C
authors.lastname: Marco
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
authors.forename: Antonio
authors.initials: A
authors.lastname: Entrena
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002794:Choline / Q000378:metabolism*; D002797:Choline Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D000255:Adenosine Triphosphate; D002797:Choline Kinase; D002794:Choline