Quantitative structure–activity relationships for a series of symmetrical bisquaternary anticancer compounds Original Research Article

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 σR and σR+ descriptors for the diallylamino, pyrrolidino, piperidino and perhydroazepino groups and σR for the N-methylanilino moiety, were estimated by 13C NMR spectroscopy in a simple, fast 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 pIC50=6.50, experimental pIC50=6.46).