Multidrug resistance (MDR) mediated by P-glycoprotein is one of the best characterized transporter-mediated
barriers to successful cancer chemotherapy. In an attempt to find MDR-reversing agents, a series of novel acridine derivatives
were synthesized and evaluated for their in vitro antiproliferative activities against K562 and K562/ADM cells.
Some of these compounds showed superior MDR-reversing activities than Amsacrine, the reference compound. Structureactivity
relationships (SAR) of these compounds indicated that the N, N-diethylamine moiety had an affect on the in vitro
antiproliferative activity. Interestingly, the compounds bearing N, N-diethylamine moiety showed higher growthinhibitory
activity against K562/ADM cells than K562 cells. The high duplex DNA binding affinity and inhibition of
topoisomerase of these acridine compounds are maintained which were confirmed by fluorescent quenching and DNA
topoisomerase II cleavage assay, respectively. Moreover, several compounds were examined for their ability to increase
the accumulation of rhodamine 123 in K562 and K562/ADM cells, and the result suggested that they may be inhibitors for
P-glycoprotein. Our study suggested that acridine framework is a potentially interesting scaffold for developing novel
Keywords: Acridine derivative, structure-activity relationships, P-glycoprotein, multidrug resistance.
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