title: QSAR-derived choline kinase inhibitors: how rational can antiproliferative drug design be?
abstract: This review presents an overview of Choline Kinase (ChoK) inhibitors with antiproliferative activity. The consideration of ChoK as a novel target for the development of new anticancer drugs is justified. The synthesis of several derivatives based on structural modifications of hemicholinium-3 (HC-3) is not accompanied by potentiation of the neurological toxicity of HC-3. The increment of both ChoK inhibitory and antiproliferative activities was successfully obtained by the two following changes: a) substitution of the oxazonium moiety of HC-3 by several aromatic heterocycles, and b) using the 1,2-ethylene(bisbenzyl) moiety instead of the 4,4'-biphenyl fragment. In an attempt to understand the ChoK inhibitory activity, a quantitative structure-activity relationship was developed. The QSAR equations have described the forces involved in quantitative terms. The electron characteristic of the substituent at position 4 of the heterocycle and the lipophilic character of the whole molecule were found to significantly affect the antitumour activity in compounds 17-95. Trispyridinium compounds 91-95 are more potent than the bispyridinium ones 87-89 as ChoK inhibitors. Nevertheless, 91-95 are less active than 87-89 as antiproliferative agents because the latter show better lipophilicities to cross the cytosolic membranes. Inhibition of the growth of human tumours in nude mice has been demonstrated: Antitumour activity of compound 64 against human HT-29 produced a decrease of up to 70% in the size of the tumour in nude mice. These results indicate that ChoK can be used as a general target for anticancer drug design against Ras-dependent tumourigenesis.
authors.affiliation: Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/ Campus de Cartuja, s/n, 18071 Granada, Spain. jmcampos@ugr.es
authors.forename: J
authors.initials: J
authors.lastname: Campos
authors.forename: M C
authors.initials: MC
authors.lastname: Núñez
authors.forename: A
authors.initials: A
authors.lastname: Conejo-García
authors.forename: R M
authors.initials: RM
authors.lastname: Sánchez-Martín
authors.forename: R
authors.initials: R
authors.lastname: Hernández-Alcoceba
authors.forename: A
authors.initials: A
authors.lastname: Rodríguez-González
authors.forename: J C
authors.initials: JC
authors.lastname: Lacal
authors.forename: M A
authors.initials: MA
authors.lastname: Gallo
authors.forename: A
authors.initials: A
authors.lastname: Espinosa
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006426:Hemicholinium 3 / Q000494:pharmacology; D006801:Humans; D021281:Quantitative Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006426:Hemicholinium 3; D002797:Choline Kinase