β-Secretase (BACE1)-inhibiting C-methylrotenoids from Abronia nana suspension cultures

Bioorg Med Chem Lett. 2014 Jul 1;24(13):2945-8. doi: 10.1016/j.bmcl.2014.04.060. Epub 2014 Apr 24.

Abstract

Suspension cultures of Abronia nana were established to produce C-methylisoflavones. A new C-methylrotenoid, named abronione A (2), was isolated along with three known rotenoids, boeravinone D (1), boeravinone A methyl ether (3), and mirabijalone D (4). The IC50 values of compounds 1, 2, and 4 on β-secretase (BACE1) were 4.77, 62.21, and 4.24 μM, respectively, whereas 3 was inactive. At concentrations up to 1.0 mM, the compounds did not inhibit other proteases such as trypsin, chymotrypsin, and elastase, indicating that they were specific inhibitors of β-secretase. Compounds 1 and 4 were non-competitive inhibitors based on the Dixon plot and with Ki values of 5.01 and 4.28 μM, respectively. At 50 μM, compound 4 inhibited Aβ1-42 production by 43.7% in APPSW-N2a cells.

Keywords: Abronia nana; Abronione A; C-Methylrotenoid; β-Secretase inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors*
  • Amyloid Precursor Protein Secretases / metabolism
  • Aspartic Acid Endopeptidases / antagonists & inhibitors*
  • Aspartic Acid Endopeptidases / metabolism
  • Dose-Response Relationship, Drug
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / isolation & purification
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Isoflavones / chemistry
  • Isoflavones / isolation & purification
  • Isoflavones / pharmacology*
  • Molecular Structure
  • Nyctaginaceae / chemistry*
  • Structure-Activity Relationship

Substances

  • Enzyme Inhibitors
  • Isoflavones
  • Amyloid Precursor Protein Secretases
  • Aspartic Acid Endopeptidases
  • BACE1 protein, human