Synthesis of uronic-noeurostegine--a potent bacterial β-glucuronidase inhibitor

Org Biomol Chem. 2011 Oct 26;9(22):7807-13. doi: 10.1039/c1ob06038d. Epub 2011 Sep 27.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Cattle
  • Chemistry, Pharmaceutical / methods*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Escherichia coli / drug effects
  • Escherichia coli / enzymology
  • Escherichia coli Proteins / antagonists & inhibitors*
  • Escherichia coli Proteins / metabolism
  • Glucuronidase / antagonists & inhibitors*
  • Glucuronidase / metabolism
  • Inhibitory Concentration 50
  • Intestines / drug effects
  • Intestines / enzymology
  • Lactase / metabolism
  • Liver / drug effects
  • Liver / enzymology
  • Models, Molecular
  • Nortropanes / chemical synthesis*
  • Nortropanes / pharmacology
  • Protein Binding
  • Rats
  • Species Specificity
  • Trehalase / antagonists & inhibitors
  • Trehalase / metabolism
  • Uronic Acids / chemistry

Substances

  • Enzyme Inhibitors
  • Escherichia coli Proteins
  • Nortropanes
  • Uronic Acids
  • noeurostegine
  • Lactase
  • Trehalase
  • Glucuronidase