QSAR-derived Choline Kinase inhibitors:: How rational can antiproliferative drug design be?

被引:33
作者
Campos, J
Núñez, MC
Conejo-García, A
Sánchez-Martín, RM
Hernández-Alcoceba, R
Rodríguez-González, A
Lacal, JC
Gallo, MA
Espinosa, A
机构
[1] Fac Farm, Dept Quim Farmaceut & Organ, Granada 18071, Spain
[2] CSIC, Inst Invest Biomed, E-28029 Madrid, Spain
关键词
Choline Kinase inhibitors; antitumour drugs; bisquaternary heterocyclic compounds; Hammett parameters; lipophilicity; QSAR; frontier orbitals;
D O I
10.2174/0929867033457539
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 17-9. 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.
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页码:1095 / 1112
页数:18
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