title: Synthesis and biological activities of a 3'-azido analogue of Doxorubicin against drug-resistant cancer cells.
abstract: Doxorubicin (DOX), an anthracycline antibiotic, is one of the most active anticancer chemotherapeutic agents. The clinical use of DOX, however, is limited by the dose-dependant P-glycoprotein (P-gp)-mediated resistance. Herein, a 3'-azido analogue of DOX (ADOX) was prepared from daunorubicin (DNR). ADOX exhibited potent antitumor activities in drug-sensitive (MCF-7 and K562) and drug-resistant cell lines (MCF-7/DNR, K562/DOX), respectively. The drug resistance index (DRI) values of ADOX were much lower than that of DOX. The cytotoxicity experiments of ADOX or DOX against K562/DOX, with or without P-gp inhibitor, indicated that ADOX circumvents resistance by abolishing the P-gp recognition. This conclusion was further supported by drug influx/efflux flow cytometry experiments, as well as by molecular docking of ADOX to P-gp. In vivo animal tests, ADOX exhibited higher activity and less toxicity than DOX. The current data warranted ADOX for additional pre-clinical evaluations for new drug development.
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.|Department of Chemistry and Biochemistry, The Ohio State University, Ohio 43210, USA.|Jinan Central Hospital Affiliated to Shandong University, Jinan 250011, China.
authors.forename: Shuwen
authors.initials: S
authors.lastname: Yu
authors.affiliation: College of Chemistry and Environmental Sciences, Henan Normal University, Xinxiang 453002, China.
authors.forename: Guisheng
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, Ohio 43210, USA.
authors.forename: Wenpeng
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan 250011, China.
authors.forename: Huanhua
authors.initials: H
authors.lastname: Luo
authors.affiliation: Jinan Central Hospital Affiliated to Shandong University, Jinan 250011, China.
authors.forename: Liyun
authors.initials: L
authors.lastname: Qiu
authors.affiliation: College of Chemistry and Environmental Sciences, Henan Normal University, Xinxiang 453002, China.
authors.forename: Qingfeng
authors.initials: Q
authors.lastname: Liu
authors.affiliation: College of Pharmacy, The University of Michigan, Michigan 48109, USA.
authors.forename: Duxin
authors.initials: D
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Biochemistry, The Ohio State University, Ohio 43210, USA.|College of Pharmacy, Nan Kai University, Tianjin 300071, China.
authors.forename: Peng-George
authors.initials: PG
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China.
authors.forename: Fengshan
authors.initials: F
authors.lastname: Wang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000494:pharmacology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009369:Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: C508990:3'-azidodaunorubicin; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D001386:Azides; D004317:Doxorubicin; D003630:Daunorubicin