Design, Synthesis, and Evaluation of the Multidrug Resistance-Reversing Activity of d-Glucose Mimetics of Hapalosin

When five substituents of hapalosin were placed on D-glucose, molecular modeling revealed that the substituents on mimetics 2 and 3 occupy similar spatial positions as the corresponding substituents on hapalosin. Mimetic 3 and all the glucopyranoside intermediates generated in its synthesis were assessed for their ability to reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp) or the multidrug resistance-associated protein (MRP). None of the sugar compounds were as effective as hapalosin in inhibiting P-gp in cytotoxicity and drug accumulation assays using MCF-7/ADR cells. By contrast, four D-glucose compounds exhibited similar efficacy as hapalosin in antagonizing MRP in cytotoxicity assays with HL-60/ADR cells.