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Synthesis of uronic-Noeurostegine – a potent bacterial β-glucuronidase inhibitor†‡
Tina S. Rasmussen,Shinpei Nakagawa,Atsushi Kato,Henrik H. Jensen
Organic & Biomolecular Chemistry Pub Date : 08/12/2011 00:00:00 , DOI:10.1039/C1OB06038D
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. coliβ-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.

Graphical abstract: Synthesis of uronic-Noeurostegine – a potent bacterial β-glucuronidase inhibitor
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