title: Synthesis of simple heparanase substrates.
abstract: Heparanase degrades heparan sulfate (HS) chains on proteoglycans; elevated levels of heparanase expression correlate with tumour cell metastatic potential and vascularity, and reduced post-operative survival of cancer patients. Consequently, heparanase expression is considered a biomarker for cancer detection. Although several heparanase assays have been developed, most require the preparation of heterogeneous, (radio)labelled HS substrates and rely on the separation of enzymatically-degraded products on the basis of molecular size. In studies directed towards the development of a more direct heparanase assay, a series of glucuronides and glycosyl glucuronides were synthesised as putative heparanase substrates. These compounds were designed with various aryl aglycones that could be measured spectrophotometrically upon hydrolysis of the glycosidic linkage by heparanase. It was found that the N-sulfated 4-nitrophenyl glycosyl glucuronide 24 and the N-sulfated methylumbelliferyl glycosyl glucuronide 26 were hydrolysed by recombinant human heparanase. These compounds represent the simplest substrates of heparanase reported to date.
authors.affiliation: Institute for Glycomics, Griffith University, Gold Coast Campus, Queensland 4222, Australia.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Pearson
authors.forename: Milton J
authors.initials: MJ
authors.lastname: Kiefel
authors.forename: Vito
authors.initials: V
authors.lastname: Ferro
authors.forename: Mark
authors.initials: M
authors.lastname: von Itzstein
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002236:Carbohydrate Conformation; D002855:Chromatography, Thin Layer; D015195:Drug Design; D005966:Glucuronidase / Q000235:genetics / Q000378:metabolism*; D020719:Glucuronides / Q000138:chemical synthesis / Q000378:metabolism; D006031:Glycosylation; D006497:Heparan Sulfate / Q000378:metabolism; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000175:diagnosis / Q000201:enzymology*; D011509:Proteoglycans / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism*; D012996:Solutions; D013379:Substrate Specificity; D014407:Tumor Cells, Cultured; D000099175:Heparanase
chemical_list: D014408:Biomarkers, Tumor; D005966:Glucuronidase; D020719:Glucuronides; D006497:Heparan Sulfate; D011509:Proteoglycans; D011994:Recombinant Proteins; D012996:Solutions; D000099175:Heparanase