title: Synthesis of uronic-noeurostegine--a potent bacterial β-glucuronidase inhibitor.
abstract: Inhibition of β-glucuronidases has recently been shown to be useful in alleviating drug toxicity for common colon cancer chemotherapeutic CPT-11 (also called Irinotecan). We have prepared a new compound of the nortropane-type, uronic-Noeurostegine, and demonstrated that this is a competitive and potent E. coli β-glucuronidase inhibitor, while inhibition of the mammalian β-glucuronidase from bovine liver was found to be less significant. Although not intended, two other compounds having N-ethyl and N-(4-hydroxybutyl) substituents were also prepared in this study due to the sluggish debenzylation in the final step. The N-substituents are believed to come from reaction with the solvents used being ethanol and THF, respectively. These compounds also inhibited the two β-glucuronidases albeit to a lesser extent compared to the parent compound. Noeurostegine and the three uronic-noeurostegines were additionally evaluated as inhibitors against a wide panel of glycosidases with the former showing potent inhibition of rat intestinal lactase and trehalase, whereas the latter was found to be inactive.
authors.affiliation: Department of Chemistry, Aarhus University, Aarhus C, Denmark.
authors.forename: Tina S
authors.initials: TS
authors.lastname: Rasmussen
authors.forename: Heidi
authors.initials: H
authors.lastname: Koldsø
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Birgit
authors.initials: B
authors.lastname: Schiøtt
authors.forename: Henrik H
authors.initials: HH
authors.lastname: Jensen
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005966:Glucuronidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020128:Inhibitory Concentration 50; D007422:Intestines / Q000187:drug effects / Q000201:enzymology; D043322:Lactase / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D009662:Nortropanes / Q000138:chemical synthesis* / Q000494:pharmacology; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D014198:Trehalase / Q000037:antagonists & inhibitors / Q000378:metabolism; D014574:Uronic Acids / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D029968:Escherichia coli Proteins; D009662:Nortropanes; D014574:Uronic Acids; C547946:noeurostegine; D043322:Lactase; D014198:Trehalase; D005966:Glucuronidase