Aminopropylindenes derived from Grundmann's ketone as a novel chemotype of oxidosqualene cyclase inhibitors

Eur J Med Chem. 2013 May:63:758-64. doi: 10.1016/j.ejmech.2013.03.002. Epub 2013 Mar 14.

Abstract

A series of aminopropylindenes, designed as mimics of a cationic high energy intermediate in the oxidosqualene cyclase(1) (OSC)-mediated cyclization of 2,3-oxidosqualen to lanosterol was prepared from Grundmann's ketone. Screening on OSCs from five different organisms revealed interesting activities and selectivities of some of the compounds. A N,N-dimethylaminopropyl derivative showed promising inhibition of Trypanosoma cruzi OSC in combination with low cytotoxicity, and showed significant reduction of cholesterol biosynthesis in a human cell line.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Arabidopsis / drug effects
  • Arabidopsis / enzymology
  • Biocatalysis / drug effects
  • Cell Survival / drug effects
  • Cholesterol / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / metabolism
  • Enzyme Inhibitors / pharmacology*
  • HL-60 Cells
  • Humans
  • Inhibitory Concentration 50
  • Intramolecular Transferases / antagonists & inhibitors*
  • Intramolecular Transferases / metabolism
  • Ketones / chemistry*
  • Ketones / metabolism
  • Lanosterol / chemistry
  • Lanosterol / metabolism
  • Models, Chemical
  • Molecular Structure
  • Plant Proteins / antagonists & inhibitors
  • Plant Proteins / metabolism
  • Protozoan Proteins / antagonists & inhibitors
  • Protozoan Proteins / metabolism
  • Squalene / chemistry
  • Squalene / metabolism
  • Trypanosoma cruzi / drug effects
  • Trypanosoma cruzi / enzymology

Substances

  • Enzyme Inhibitors
  • Ketones
  • Plant Proteins
  • Protozoan Proteins
  • Lanosterol
  • Squalene
  • Cholesterol
  • Intramolecular Transferases
  • lanosterol synthase