ZFIN ID: ZDB-PUB-090828-1
High-Content Analysis of Cancer-Cell-Specific Apoptosis and Inhibition of in Vivo Angiogenesis by Synthetic (-)-Pironetin and Analogs
Vogt, A., McPherson, P.A., Shen, X., Balachandran, R., Zhu, G., Raccor, B.S., Nelson, S.G., Tsang, M., and Day, B.W.
Date: 2009
Source: Chemical Biology & Drug Design   74(4): 358-368 (Journal)
Registered Authors: Tsang, Michael
Keywords: angiogenesis, high-content screening, multi-drug resistance, pironetin, zebrafish
MeSH Terms:
  • Angiogenesis Inhibitors/chemical synthesis
  • Angiogenesis Inhibitors/chemistry*
  • Angiogenesis Inhibitors/pharmacology
  • Animals
  • Apoptosis*
  • CHO Cells
  • Cell Line, Tumor
  • Cricetinae
  • Cricetulus
  • Drug Resistance, Neoplasm
  • Drug Screening Assays, Antitumor
  • Humans
  • Microtubules/metabolism
  • Mitosis/drug effects
  • Neovascularization, Physiologic/drug effects*
  • Pyrones/chemical synthesis
  • Pyrones/chemistry*
  • Pyrones/pharmacology
  • Tubulin Modulators/chemical synthesis
  • Tubulin Modulators/chemistry*
  • Tubulin Modulators/pharmacology
  • Zebrafish
PubMed: 19691472 Full text @ Chem. Biol. Drug Des.
The natural product (-)-pironetin is a structurally simple small molecule microtubule-perturbing agent whose biological activities appear to be exquisitely dependent on defined stereochemistry and the presence of an eletrophilic alpha,beta-unsaturated lactone moiety. We used alkaloid-catalyzed acyl halide-aldehyde cyclocondensation reactions in asymmetric total syntheses of (-)-pironetin and three synthetic analogs, and evaluated their biological activities by high-content analysis in cell culture and in a zebrafish model. Synthetic (-)-pironetin and 2,3-dihydro-3-hydroxypironetin caused mitotic arrest and programmed cell death in human lung cancer cells but not in normal lung fibroblasts, had nanomolar growth inhibitory activity in multi-drug resistant cells, and inhibited neovascularization in zebrafish embryos. Synthetic (-)-pironetin delayed the onset but increased the extent of tubulin assembly in vitro. The data illustrate the power of acyl halide-aldehyde cyclocondensation to generate biologically active synthetic analogs of stereochemically complex targets and suggest that (-)-pironetin and 2,3-dihydro-3-hydroxypironetin possess unique properties that may bestow them with advantages over existing microtubule-perturbing agents in the context of a whole organism or under conditions of multi-drug resistance.