EFFECT OF STRUCTURAL MODIFICATIONS OF ANTHRACYCLINE AGAINST DRUG-SENSITIVE AND RESISTANT CANCER CELLS By

Purpose: Many anthracycline anticancer drugs contain carbohydrate moieties as a part of their chemical structure. Research studies have suggested that the sugar moiety of these anthracyclines play an important role in determining the biological and pharmacological activities of the drug. The clinical application of anthracycline antibiotics, daunorubicin (DNR) and doxorubicin is limited by the development of multidrug resistance (MDR) in cancer therapy. To overcome multidrug resistance, we synthesized daunorubicin derivatives with disaccharides, monosaccharide bearing azido (d9) and triazole groups (compounds d10-d13), monosaccharide with uncommon (DNR1 to DNR 6, and aglycon compound (DNR-A). Methods: The anticancer activity of these compounds was examined in drug-sensitive leukemia K562 cells and drug-resistant K562/dox cells by MTS assay. MTS in the presence and absence of CsA, a potent inhibitor of P-glycoprotein, were conducted to measure drug uptake and efflux mediated by P-gp. Results: Compounds with various terminal 2,6-dideoxy sugars (d1, d3, d5, and d8) showed 30 to 60-fold higher anticancer activity than compounds with terminal 2deoxyor 6-deoxysugar (compound d6 and d7). This suggests that 2”-OH or 6”-OH groups in terminal sugar decrease its anticancer activity. Compound (d9) with azido deoxysugar showed potent anticancer activity in drug-sensitive K562 cells (IC50 of 0.075uM). Compared to DNR, compound (d9) is more active than DNR against K562 drug-resistant cells. The drug resistance index (DRI) value of compound (d9) is 10-fold less than that of DNR. P-gp inhibitor CsA did not change cell killing effects of compound d9 at 1uM concentration, while it significantly increased DNR’s cell killing effect by more than 2-fold. These results indicate that compound (d9) may no longer be a P-gp