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

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 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.

• Authors: Andreas Vogt, Peter A McPherson, Xiaoqiang Shen, Raghavan Balachandran, Guangyu Zhu, Brianne S Raccor, Scott G Nelson, Michael Tsang, Billy W Day
• Journal: Chemical biology & drug design (Chem Biol Drug Des) Vol. 74 Issue 4 Pg. 358-68 (Oct 2009) ISSN: 1747-0285 [Electronic] England
• PMID: 19691472 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Angiogenesis Inhibitors
• Pyrones
• Tubulin Modulators
• pironetin

Topics

• Angiogenesis Inhibitors (chemical synthesis, chemistry, 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, chemistry, pharmacology)
• Tubulin Modulators (chemical synthesis, chemistry, pharmacology)
• Zebrafish