J. Campos, M. C. Nunez, A. Conejo-Garcia, R. M. Sanchez-Martin, R. Hernandez-Alcoceba, A. Rodriguez-Gonzalez, J. C. Lacal, M. A. Gallo and A. Espinosa Pages 1095 - 1112 ( 18 )
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.
choline kinase inhibitors,antitumour drugs,bisquaternary heterocyclic compounds,hammett parameters,lipophilicity,qsar,frontier orbitals
, , , , , , , , Departamento de Quimica Farmaceutica y Organica, Facultad de Farmacia, c / Campus de Cartuja,s / n, 18071 Granada, Spain.