Chemoenzymatic synthesis, structural study and biological activity of novel indolizidine and quinolizidine iminocyclitols

Org Biomol Chem. 2012 Aug 21;10(31):6309-21. doi: 10.1039/c2ob25943e. Epub 2012 Jun 26.

Abstract

The synthesis, conformational study and inhibitory properties of diverse indolizidine and quinolizidine iminocyclitols are described. The compounds were chemo-enzymatically synthesized by two-step aldol addition and reductive amination reactions. The aldol addition of dihydroxyacetone phosphate (DHAP) to N-Cbz-piperidine carbaldehyde derivatives catalyzed by L-rhamnulose 1-phosphate aldolase from Escherichia coli provides the key intermediates. The stereochemical outcome of both aldol addition and reductive amination depended upon the structure of the starting material and intermediates. The combination of both reactions furnished five indolizidine and six quinolizidine type iminocyclitols. A structural analysis by NMR and in silico density functional theory (DFT) calculations allowed us to determine the population of stereoisomers with the trans or cis ring fusion, as a consequence of the inversion of configuration of the bridgehead nitrogen. The trans fusion was by far the most stable, but for certain stereochemical configurations of the 3-hydroxymethyl and hydroxyl substituents both trans and cis fusion stereoisomers coexisted in different proportions. Some of the polyhydroxylated indolizidines and quinolizidines were shown to be moderate to good inhibitors against α-L-rhamnosidase from Penicillium decumbens. Indolizidines were found to be moderate inhibitors of the rat intestinal sucrase and of the exoglucosidase amyloglucosidase from Aspergillus niger. In spite of their activity against α-L-rhamnosidase, all the compounds were ineffective to inhibit the growth of the Mycobacterium tuberculosis, the causative agent of tuberculosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde-Lyases / metabolism
  • Animals
  • Aspergillus niger / enzymology
  • Dihydroxyacetone Phosphate / chemistry
  • Dihydroxyacetone Phosphate / metabolism
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • Escherichia coli / enzymology
  • Glucan 1,4-alpha-Glucosidase / antagonists & inhibitors
  • Glucan 1,4-alpha-Glucosidase / metabolism
  • Glucosidases / antagonists & inhibitors
  • Glucosidases / metabolism
  • Glycoside Hydrolases / antagonists & inhibitors
  • Glycoside Hydrolases / metabolism
  • Indolizidines / chemistry*
  • Indolizidines / metabolism
  • Indolizidines / pharmacology*
  • Models, Molecular
  • Molecular Conformation
  • Mycobacterium tuberculosis / drug effects
  • Mycobacterium tuberculosis / growth & development
  • Penicillium / enzymology
  • Quinolizidines / chemistry*
  • Quinolizidines / metabolism
  • Quinolizidines / pharmacology*
  • Rats
  • Sucrase / antagonists & inhibitors
  • Sucrase / metabolism

Substances

  • Enzyme Inhibitors
  • Indolizidines
  • Quinolizidines
  • Dihydroxyacetone Phosphate
  • Glucosidases
  • Glycoside Hydrolases
  • Glucan 1,4-alpha-Glucosidase
  • alpha-L-rhamnosidase
  • Sucrase
  • Aldehyde-Lyases
  • rhamnulose-1-phosphate adolase