Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811
USA

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QSAR as a Tool for the Development of Potent Antiproliferative Agents by Inhibition of Choline Kinase

Author(s): M. C. Nunez, A. Conejo-Garcia, R. M. Sanchez-Martin, M. A. Gallo, A. Espinosa, J. M. Campos.

Abstract:

The identification of the molecular components involved in the aberrant processes that control proliferation, differentiation and apoptosis, is necessary for the development of chemotherapeutic interventions to restore or to destroy selectively the transformed cells. The discovery of new chemotherapeutic agents is probably one of the most reliable ways to improve our success against cancer, and intelligent drug design is a key factor to achieve this goal. Thus, the identification of novel targets for anticancer drug discovery is needed. Here we provide evidence that choline kinase (ChoK) is a novel target for the design of antitumor drugs. In this review we present the evolution of ChoK inhibitors by using the Hansch approach, starting from hemicholinium-3 (HC-3) as a lead compound. To start with we synthesized and evaluated ten bis-quaternary derivatives, in which the modifications affect both the spacer and the two cationic heads of the prototype. In the second phase 56 biscationic dibromides with distinct polar heads [bis(4-substituted)pyridinium, bis(4-substituted)quinolinium, and bisisoquinolinium moieties] and several spacers were synthesized and assayed for biological activity. This oriented synthesis produced 45 inhibitors of ChoK with antitumor activity against the HT-29 cell line. Finally, 40 bisquinolinium compounds were prepared and the corresponding QSAR equation was obtained for the whole set of compounds for the antiproliferative activity, the electronic parameter R of R4, the molar refractivity of R8, and the lipophilic parameters clog P and πlinker. The most potent antiproliferative agent so far described shows IC50 = 0.20 μM, while its theoretical value is 0.45 μM.

Keywords: Antiproliferative agents, electrostatic effects, choline kinase, frontier orbitals, hammet constants, lipophilicity, QSAR

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Article Details

VOLUME: 3
ISSUE: 4
Year: 2007
Page: [297 - 313]
Pages: 17
DOI: 10.2174/157340907782799354
Price: $58