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.

Marine Natural Products as Models to Circumvent Multidrug Resistance

“…Several syntheses for 80 and its respective analogs have been reported, with the purpose of obtaining compounds with similar or better MDR reversal activity. Some of the analogs did not fulfill this objective; for example, the glucose mimic of hapalosin (80) and 8-deoxyhapalosin, the triamide analogs, and N-demethylhapalosin 81 possessing a trans-amide, exhibited weak MDR reversal activity [180][181][182]. Through SAR studies, proline-containing congeners (82 and 83) were found to be more potent against MCF-7/ADR cells than 81 [182].…”

“…At 20 μM concentration, compound 80 significantly enhanced the accumulation of [ 3 H]-paclitaxel in SKVLB1 cells, and exhibited a similar activity to verapamil in breast cancer cell MCF-7/ADR in the range of 1.5-10 μM [180,181]. Several syntheses for 80 and its respective analogs have been reported, with the purpose of obtaining compounds with similar or better MDR reversal activity.…”

“…It was postulated that the cis-peptide might be essential to express the MDR-reversing activity, and the bioactive function of 80 and analogs depends on the S-cis or S-trans configuration [182,184]. Also, a free hydroxyl and aromatic groups may be important for the anti-MDR activity of hapalosin (80) At 20 µM concentration, compound 80 significantly enhanced the accumulation of [ 3 H]-paclitaxel in SKVLB1 cells, and exhibited a similar activity to verapamil in breast cancer cell MCF-7/ADR in the range of 1.5-10 µM [180,181]. Several syntheses for 80 and its respective analogs have been reported, with the purpose of obtaining compounds with similar or better MDR reversal activity.…”

Peptidomimetics, Glycomimetics and Scaffolds from Carbohydrate Building Blocks

“…Sugar amino acids have been classified as dipeptide isosteres by Kessler, showing that they can be considered as scaffolds for synthesis of type-I peptidomimetics also. In addition to the cases where saccharides have been investigated as somatostatin mimetics and HIV-protease inhibitors, they have been applied to the synthesis of cyclic endothelin antagonists, [16] thrombin inhibitors, [17] multidrug-resistant-associated protein inhibitor, [18] cytomegalovirus inhibitors, [19] integrin ligands, [20] fibrinogen receptor ligands, [21] LPA agonists and antagonists, [22] rhodopeptin mimetics, [23] cysteine protease calpain inhibitors [24] and inhibitors of the growth of human cell lines. [25] Synthesis of a β-Turn Mimetic Based on 1-Deoxymannojirimycin Somatostatin (SST) is a tetradecapeptide that regulates, through binding to its receptors (SSTR) a number of processes including the release of growth hormone and other pituitary hormones.…”

Syntheses of Peptidomimetics Based on Pyranose and Polyhydroxylated Piperidine Scaffolds

“…depsipeptide hapalosin 29 to target cancer [25]. Cancer chemotherapy treatments can provide temporary clinical improvement, but tumour cells that endure the initial therapeutic attack often recover with greater resistance to both the original and other structurally unrelated drugs.…”