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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 3.0).

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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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