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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

QSAR-Derived Choline Kinase Inhibitors: How Rational can Antiproliferative Drug Design Be?

Author(s): 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

Volume 10 , Issue 13 , 2003

Page: [1095 - 1112] Pages: 18

DOI: 10.2174/0929867033457539

Price: $65


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.

Keywords: choline kinase inhibitors, antitumour drugs, bisquaternary heterocyclic compounds, hammett parameters, lipophilicity, qsar, frontier orbitals

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