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

Tam Q. Dinh; Charles D. Smith; Xiaohui Du; Robert W. Armstrong

doi:10.1021/jm970709p

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

Tam Q. Dinh, Charles D. Smith, Xiaohui Du, Robert W. Armstrong

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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.

Original language	English (US)
Pages (from-to)	981-987
Number of pages	7
Journal	Journal of Medicinal Chemistry
Volume	41
Issue number	6
DOIs	https://doi.org/10.1021/jm970709p
State	Published - Mar 12 1998

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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

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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AU - Dinh, Tam Q.

AU - Smith, Charles D.

AU - Du, Xiaohui

AU - Armstrong, Robert W.

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

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