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Int. J. Mol. Sci. 2012, 13(3), 3671-3684; doi:10.3390/ijms13033671

Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells

2,6,*  and 1,*
1 School of Pharmaceutical Sciences, Shandong University, Jinan 250012, China 2 Department of Chemistry and Biochemistry, The Ohio State University, Ohio 43210, USA 3 Jinan Central Hospital Affiliated to Shandong University, Jinan 250011, China 4 College of Chemistry and Environmental Sciences, Henan Normal University, Xinxiang 453002, China 5 College of Pharmacy, The University of Michigan, Michigan 48109, USA 6 College of Pharmacy, Nan Kai University, Tianjin 300071, China
* Authors to whom correspondence should be addressed.
Received: 13 February 2012 / Revised: 7 March 2012 / Accepted: 13 March 2012 / Published: 19 March 2012
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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.
Keywords: anthracycline; Azido; multidrug resistance; ADOX; P-gp anthracycline; Azido; multidrug resistance; ADOX; P-gp
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Yu, S.; Zhang, G.; Zhang, W.; Luo, H.; Qiu, L.; Liu, Q.; Sun, D.; Wang, P.-G.; Wang, F. Synthesis and Biological Activities of a 3'-Azido Analogue of Doxorubicin Against Drug-Resistant Cancer Cells. Int. J. Mol. Sci. 2012, 13, 3671-3684.

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