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 po sitively 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 su bstitution of the bromine with piperidine. All compounds showed high M DR-modulating activity with EC50 values from 1.45-0.15 mu M Generally, activity increased with increasing number of methylene groups, whereb y it reaches a plateau for compounds with more than five methylene gro ups between the ether oxygen and the nitrogen atom. (C) 1998 Elsevier Science S.A. All rights reserved.