Synthesis and biological evaluation of a 2-aryl polyhydroxylated pyrrolidine alkaloid-based library

Bioorg Med Chem. 2008 Dec 15;16(24):10198-204. doi: 10.1016/j.bmc.2008.10.063. Epub 2008 Nov 5.

Abstract

Inspired by polyhydroxylated pyrrolidine alkaloid natural products, a 18-membered library of 2-aryl polyhydroxylated pyrrolidines has been efficiently prepared in two or three synthetic steps from the known chiral cyclic nitrones with high yield and purity and excellent stereoselectivity. The inhibitory activity of all these compounds against various glycosidase enzymes was evaluated. Interestingly, 15 and 19 show better inhibitory activities than radicamine A (20) and B (18) against alpha-glucosidases. The IC(50) values of 15 and 19 are 1.1 and 0.5 microM, respectively. In this study, we also discovered the substituent(s) on the aryl ring could affect the inhibition potency and selectivity against glycosidases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkaloids / chemical synthesis*
  • Alkaloids / chemistry
  • Alkaloids / pharmacology*
  • Drug Design
  • Glycoside Hydrolase Inhibitors*
  • Inhibitory Concentration 50
  • Pyrrolidines / chemical synthesis*
  • Pyrrolidines / chemistry
  • Pyrrolidines / pharmacology*
  • Stereoisomerism
  • alpha-Glucosidases / metabolism
  • beta-Mannosidase / antagonists & inhibitors
  • beta-Mannosidase / metabolism

Substances

  • Alkaloids
  • Glycoside Hydrolase Inhibitors
  • Pyrrolidines
  • alpha-Glucosidases
  • beta-Mannosidase