Design, synthesis, and evaluation of the multidrug resistance-reversing activity of D-glucose mimetics of hapalosin

  • J Med Chem. 1998 Mar 12;41(6):981-7. doi: 10.1021/jm970709p.
T Q Dinh  1 ,  C D Smith ,  X Du ,  R W Armstrong
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of California, Los Angeles 90095, USA.
PMID: 9526572 DOI: 10.1021/jm970709p
Abstract

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.

Products