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, molecula r modeling revealed that the substituents on mimetics 2 and 3 occupy s imilar spatial positions as the corresponding substituents on hapalosi n. Mimetic 3 and all the glucopyranoside intermediates generated in it s synthesis were assessed for their ability to reverse multidrug resis tance (MDR) mediated by P-glycoprotein (P-gp) or the multidrug resista nce-associated protein (MRP). None of the sugar compounds were as effe ctive as hapalosin in inhibiting P-gp in cytotoxicity and drug accumul ation assays using MCF-7/ADR cells. By contrast, four D-glucose compou nds exhibited similar efficacy as hapalosin in antagonizing MRP in cyt otoxicity assays with HL-60/ADR cells.