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

Affiliation

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.

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