title: Synthesis, structure-activity relationship and biological activity of acridine derivatives as potent MDR-reversing agents.
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. Structure-activity 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 growth-inhibitory 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.
authors.affiliation: Key laboratory of natural medicines and immunotechnology of Henan province, Henan University, kaifeng 475004, Henan, P.R. China. hdky@henu.edu.cn.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Wang
authors.forename: Tianwei
authors.initials: T
authors.lastname: Luo
authors.forename: Shaobin
authors.initials: S
authors.lastname: Li
authors.forename: Yahong
authors.initials: Y
authors.lastname: Zhhang
authors.forename: Chaojie
authors.initials: C
authors.lastname: Wang
authors.forename: Jin
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000677:Amsacrine / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D013329:Structure-Activity Relationship
chemical_list: D000166:Acridines; D000970:Antineoplastic Agents; D000677:Amsacrine