Studies on propafenone-type modulators of multidrug resistance VI. Synthesis and pharmacological activity of compounds with varied spacer length between the central aromatic ring and the nitrogen atom

Abstract

A series of propafenone-type modulators of multidrug resistance (MDR) with varied spacer length between the central aromatic ring and the positively chargeable nitrogen atom was synthesized and tested for their ability to block P-glycoprotein-mediated transport of daunomycin out of tumor cells. Synthesis was achieved by O-alkylation of o-hydroxy-3-phenylpropiophenone with dibromoalkanes and subsequent nucleophilic substitution of the bromine with piperidine. All compounds showed high MDR-modulating activity with EC 50 values from 1.45–0.15 μM. Generally, activity increased with increasing number of methylene groups, whereby it reaches a plateau for compounds with more than five methylene groups between the ether oxygen and the nitrogen atom.