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.
Dinh
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Department of Chemistry and Biochemistry, University of California, Los Angeles 90095, USA.
Smith
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Du
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Armstrong
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D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors*; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors*; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides; D015195:Drug Design; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005947:Glucose / Q000737:chemistry*; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology*; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology*; D018716:Molecular Mimicry; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014407:Tumor Cells, Cultured
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D047630:Depsipeptides; D005947:Glucose; D007769:Lactams; D007783:Lactones; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C111358:hapalosin