Quantitative structure-activity relationships for a series of symmetrical bisquaternary anticancer compounds

56 biscationic dibromides with distinct polar heads [bis(4-substituted)pyridinium. bis(4-aminoquinolinium). bisquinolinium, and bisisoquinolinium moieties] and several spacers between the two charged nitrogen atoms were synthesised. This oriented synthesis produced 45 inhibitors of choline kinase with antitumour activity against the HT-29 cell line. In an attempt to understand the antiproliferative activity, a quantitative structure-activity relationship was developed. The unknown sigma(R) and sigma(R)(+) descriptors for the diallylamino. pyrrolidino, piperidino and perhydroazepino groups and sigma(R) For the N-methylanilino moiety. were estimated by C-13 NMR spectroscope in a simple. Cast and reproducible manner. The electron characteristic of the substituent at position 4 of the heterocycle and the theoretical lipophilic character of the whole molecule were found to significantly affect the antitumour activity. 1,1'-[Ethylenebis(benzene-1.4-diylmethylene)]bis[4-(N-methylanilino)pyridinium] dibromide is the most active compound of the series so far described and shows a reasonable agreement between predicted and observed antiproliferative data (predicted pIC(50) = 6.50, experimental pIC(50) = 6.46). (C) 2002 Elsevier Science Ltd. All rights reserved.