Discovery of a daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance

Lanyan Fang, Guisheng Zhang, Chenglong Li, Xincheng Zheng, Lizhi Zhu, Jim J. Xiao, Gergely Szakacs, Janos Nadas, Kenneth K. Chan, Peng George Wang, Duxin Sun

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Abstract

Anthracyclines are considered to be some of the most effective anticancer drugs for cancer therapy. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application. We hypothesize that direct modifications of the sugar moiety of anthracyclines avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance. Daunorubicin (DNR) analogues with sugar modifications were synthesized by directly transforming the amino group of DNR to an azido group or triazole group. Molecular docking showed that the lead compound (3′-azidodaunorubicin, ADNR) averts P-gp binding, while daunorubicin (DNR) extensively interacts with multidrug-resistance (MDR) protein through H-bonds and electrostatic interactions. FACS assay demonstrated that these new compounds abolished P-gp drug efflux and accumulated high intracellular concentration in the drug-resistant leukemia K562/Dox. P-gp inhibition by CsA confirmed that these new analogues are no longer P-gp substrates. ADNR exhibited potent anticancer activity in both drug-sensitive (K562) and drug-resistant leukemia cells (K562/Dox), with a 25-fold lower drug resistance index than DNR. An in vivo xenograft model demonstrated that ADNR showed more than 2.5-fold higher maximum growth inhibition rate against drug-resistant cancers and significant improvement for animal survival rate versus DNR. No significant body weight reduction in mice was observed for ADNR at the maximum tolerable dose, as compared to more than 70% body weight reduction for DNR. These data suggest that sugar modifications of anthracyclines avert P-gp binding, abolish P-gp-mediated drug efflux, increase intracellular drug concentration, and thus overcome P-gp-mediated drug resistance in cancer therapy.

Original languageEnglish
Pages (from-to)932-941
Number of pages10
JournalJournal of Medicinal Chemistry
Volume49
Issue number3
DOIs
Publication statusPublished - Feb 9 2006

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Fang, L., Zhang, G., Li, C., Zheng, X., Zhu, L., Xiao, J. J., Szakacs, G., Nadas, J., Chan, K. K., Wang, P. G., & Sun, D. (2006). Discovery of a daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance. Journal of Medicinal Chemistry, 49(3), 932-941. https://doi.org/10.1021/jm050800q