title: Modifying the sugar moieties of daunorubicin overcomes P-gp-mediated multidrug resistance.
abstract: Anthracyclines are widely used in patients for anticancer activity. However, one of the limitations for their clinical use is P-gp-mediated drug resistance in cancer therapy. We hypothesize that modified anthracyclines will retain their anticancer activity, avert P-gp binding, and thus overcome P-gp-mediated drug resistance. Twenty-five daunorubicin analogues were synthesized with slight structure modifications in sugar moieties. Molecular docking, cytotoxicity, and P-gp inhibition assays in drug-resistant leukemia cells (K562/Dox) were used to identify several candidates that avert binding to multidrug-resistant protein (MsbA) and overcome drug resistance. Molecular docking showed that daunorubicin bound to the cavity between the intracellular domain (ICD) and nucleoside binding domain (NBD) of MsbA, which might be the "entry site" for the transport of its substrate. The molecular docking accurately predicted the substrates of multidrug-resistant protein. Several aspects are important for daunorubicin analogue binding to MsbA: (1) the substitution pattern and stereochemistry of the tetracyclic ring and sugar moiety; (2) the hydrogen bond donor or acceptor capability of the substituent at C'-3 and C'-4. Molecular docking, cytotoxicity, and P-gp inhibition assays identified ADNR, ADNR-1, and ADNR-3 for averting P-gp binding and overcoming drug resistance. The replacement of C'-3-NH2 with azido group in daunorubicin not only abolishes the hydrogen bond between the sugar moiety and MsbA but also completely changes the overall binding conformation, and thus averts the binding to MsbA. Cytotoxicity assays confirmed that these compounds showed high sensitivity against drug-resistant cancer cells (K562/Dox) with P-gp overexpression. P-gp inhibition assay indeed confirms that these appropriately modified compounds avert P-gp binding and thus overcome P-gp-mediated drug resistance.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Battisti
authors.forename: Yanqiang
authors.initials: Y
authors.lastname: Zhong
authors.forename: Lanyan
authors.initials: L
authors.lastname: Fang
authors.forename: Seth
authors.initials: S
authors.lastname: Gibbs
authors.forename: Jie
authors.initials: J
authors.lastname: Shen
authors.forename: Janos
authors.initials: J
authors.lastname: Nadas
authors.forename: Guisheng
authors.initials: G
authors.lastname: Zhang
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D050260:Carbohydrate Metabolism; D016572:Cyclosporine / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D003630:Daunorubicin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D004187:Disaccharides / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D020014:K562 Cells; D009005:Monosaccharides / Q000378:metabolism; D017433:Protein Structure, Secondary
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D001426:Bacterial Proteins; D004187:Disaccharides; D009005:Monosaccharides; C079726:MsbA protein, Bacteria; D016572:Cyclosporine; D003630:Daunorubicin