Syntheses and biological activities of 3'-azido disaccharide analogues of daunorubicin against drug-resistant leukemia.
Anthracyclines, such as daunorubicin (DNR) and doxorubicin (Dox), are widely used for cancer therapy but are limited by drug resistance and cardiotoxicity. To overcome drug resistance, we synthesized a novel class of disaccharide analogues of DNR against drug-resistant leukemia. In these disaccharide analogues (1-6) the first (inner) sugar in the carbohydrate chain is a 3-azido-2,3,6-trideoxy-L-lyxo-alpha-hexopyranose; the second (outer) sugars that are linked via alpha(1-->4) to the first sugar are a series of uncommon sugars. Their cytotoxicities were examined in drug-sensitive leukemia cells K562 and doxorubicin-resistant K562/Dox cells by MTS assay. In drug-sensitive cells, compounds 1-6 were found to be active against leukemia K562 cells with IC50 in the nanomolar range (200-1100 nM), while compounds 2-5 with 2,6-dideoxy sugars showed better activity than compounds 1 and 6 with 2,3,6-trideoxy sugars. In doxorubicin-resistant K562/Dox cells, compounds 1, 3, and 5 exhibited much better activities (with IC50 between 0.29 and 2.0 microM) than DNR (with IC50 > 5 microM). Compound 3 emerged as the most active compound, showing at least 17-fold higher activity against drug-resistant cells than parent compound DNR. The IC50 values of compound 3 in both drug-sensitive and drug-resistant cells are identical, which indicates that compound 3 completely overcomes drug resistance. Structure-activity relationship (SAR) studies showed that the substitution and orientation of the 3-OH group in the second sugar significantly influence its activity against drug-resistant leukemia. These results suggest that sugar modifications of anthracyclines change their activity and overcome drug resistance.
Zhang
Guisheng
G
Department of Chemistry and Biochemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio 43210, USA.
Fang
Lanyan
L
Zhu
Lizhi
L
Zhong
Yanqiang
Y
Wang
Peng George
PG
Sun
Duxin
D
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001386:Azides / Q000138:chemical synthesis* / Q000494:pharmacology; D003630:Daunorubicin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D004187:Disaccharides / Q000138:chemical synthesis* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020014:K562 Cells; D004915:Leukemia, Erythroblastic, Acute
D000970:Antineoplastic Agents; D001386:Azides; D004187:Disaccharides; D003630:Daunorubicin