title: Anticancer bisquaternary heterocyclic compounds: a ras-ional design.
abstract: A new family of symmetrical bisquaternary compounds with semirigid linkers have shown to be highly specific for Choline Kinase (ChoK) inhibition and to exert antitumoural activity in cell lines and in mice. A three-parameter regression equation has been derived which satisfactorily describes the ex vivo inhibitory potency of ChoK of the title compounds. The electronic effect of the group at position 4 of the cationic head plays a critical role although the hydrophobic contribution, especially that of the linker, favors the ChoK inhibitory activity. The antiproliferative activity (in vitro assay) is correlated with the ChoK inhibition (ex vivo assay) through the electronic effect and a squared term of the overall lipophilicity of the molecules. We also provide in vivo evidence that ChoK is a novel target for the design of antitumoural drugs. All these results suggest that ChoK plays a crucial role in the onset of carcinogenesis.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, c/ Campus de Cartuja, s/n 18071 Granada, Spain. jmcampos@ugr.es
authors.forename: Joaquín
authors.initials: J
authors.lastname: Campos
authors.forename: Carmen
authors.initials: C
authors.lastname: Núñez
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Díaz
authors.forename: Rosario M
authors.initials: RM
authors.lastname: Sánchez
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Gallo
authors.forename: Antonio
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000737:chemistry / Q000187:drug effects*; D015195:Drug Design; D006131:Growth Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D018631:ras Proteins / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D006131:Growth Inhibitors; D006571:Heterocyclic Compounds; D018631:ras Proteins