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

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 EC50 values from 1.45-0.15 mu M 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. (C) 1998 Elsevier Science S.A. All rights reserved.