Boehmeriasin A as new lead compound for the inhibition of topoisomerases and SIRT2

Eur J Med Chem. 2015 Mar 6:92:766-75. doi: 10.1016/j.ejmech.2015.01.038. Epub 2015 Jan 20.

Abstract

Two synthetic approaches to boehmeriasin A are described. A gram scale racemic preparation is accompanied by an efficient preparation of both the pure enantiomers using the conformationally stable 2-piperidin-2-yl acetaldehyde as starting material. The anti-proliferative activity in three cancer cell lines (CEM, HeLa and L1210) and two endothelial cell lines (HMEC-1, BAEC) indicates promising activity at the nanomolar range. Topoisomerases and SIRT2 are identified as biological targets and the experimental data has been supported by docking studies.

Keywords: Boehmeriasin A; Sirtuins inhibition; Topoisomerases inhibition; Total synthesis.

MeSH terms

  • Cell Line
  • Cell Proliferation / drug effects
  • DNA Topoisomerases, Type I / metabolism
  • DNA Topoisomerases, Type II / metabolism
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Phenanthrenes / chemical synthesis
  • Phenanthrenes / chemistry
  • Phenanthrenes / pharmacology*
  • Quinolizidines / chemical synthesis
  • Quinolizidines / chemistry
  • Quinolizidines / pharmacology*
  • Sirtuin 2 / antagonists & inhibitors*
  • Sirtuin 2 / metabolism
  • Structure-Activity Relationship
  • Topoisomerase I Inhibitors / chemical synthesis
  • Topoisomerase I Inhibitors / chemistry
  • Topoisomerase I Inhibitors / pharmacology*
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology*

Substances

  • Phenanthrenes
  • Quinolizidines
  • Topoisomerase I Inhibitors
  • Topoisomerase II Inhibitors
  • boehmeriasin A
  • SIRT2 protein, human
  • Sirtuin 2
  • DNA Topoisomerases, Type I
  • DNA Topoisomerases, Type II