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Current Medicinal Chemistry


ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Synthesis, Structure-Activity Relationship and Biological Activity of Acridine Derivatives as Potent MDR-Reversing Agents

Author(s): Jianhong Wang, Tianwei Luo, Shaobin Li, Yahong Zhhang, Chaojie Wang and Jin Zhao

Volume 20 , Issue 32 , 2013

Page: [4070 - 4079] Pages: 10

DOI: 10.2174/09298673113209990187

Price: $65


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 MDR-reversing agents.

Keywords: Acridine derivative, structure-activity relationships, P-glycoprotein, multidrug resistance.

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