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 (13)C 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 pIC(50)=6.50, experimental pIC(50)=6.46).
Campos
Joaquín M
JM
Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, c/Campus de Cartuja s/n, 18071 Granada, Spain.
Núñez
María C
MC
Sánchez
Rosario M
RM
Gómez-Vidal
José A
JA
Rodríguez-González
Agustín
A
Báñez
Mónica
M
Gallo
Miguel A
MA
Lacal
Juan Carlos
JC
Espinosa
A
A
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002797:Choline Kinase / Q000037:antagonists & inhibitors; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D019073:HT29 Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D021281:Quantitative Structure-Activity Relationship
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D002797:Choline Kinase