Abstract
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.
Current Medicinal Chemistry
Title:Synthesis, Structure-Activity Relationship and Biological Activity of Acridine Derivatives as Potent MDR-Reversing Agents
Volume: 20 Issue: 32
Author(s): Jianhong Wang, Tianwei Luo, Shaobin Li, Yahong Zhhang, Chaojie Wang and Jin Zhao
Affiliation:
Keywords: Acridine derivative, structure-activity relationships, P-glycoprotein, multidrug resistance.
Abstract: 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.
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Wang Jianhong, Luo Tianwei, Li Shaobin, Zhhang Yahong, Wang Chaojie and Zhao Jin, Synthesis, Structure-Activity Relationship and Biological Activity of Acridine Derivatives as Potent MDR-Reversing Agents, Current Medicinal Chemistry 2013; 20 (32) . https://dx.doi.org/10.2174/09298673113209990187
DOI https://dx.doi.org/10.2174/09298673113209990187 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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