High-content analysis of cancer-cell-specific apoptosis and inhibition of in vivo angiogenesis by synthetic (-)-pironetin and analogs

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review

28 Scopus Citations
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Author(s)

  • Andreas Vogt
  • Peter A. McPherson
  • Xiaoqiang Shen
  • Raghavan Balachandran
  • Brianne S. Raccor
  • Scott G. Nelson
  • Michael Tsang
  • Billy W. Day

Detail(s)

Original languageEnglish
Pages (from-to)358-368
Journal / PublicationChemical Biology and Drug Design
Volume74
Issue number4
Publication statusPublished - Oct 2009
Externally publishedYes

Abstract

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 α,β-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. © 2009 John Wiley & Sons A/S.

Research Area(s)

  • Angiogenesis, High-content screening, Multi-drug resistance, Pironetin, Zebrafish

Citation Format(s)

High-content analysis of cancer-cell-specific apoptosis and inhibition of in vivo angiogenesis by synthetic (-)-pironetin and analogs. / Vogt, Andreas; McPherson, Peter A.; Shen, Xiaoqiang; Balachandran, Raghavan; Zhu, Guangyu; Raccor, Brianne S.; Nelson, Scott G.; Tsang, Michael; Day, Billy W.

In: Chemical Biology and Drug Design, Vol. 74, No. 4, 10.2009, p. 358-368.

Research output: Journal Publications and Reviews (RGC: 21, 22, 62)21_Publication in refereed journalpeer-review