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.
- Chemical Biology & Drug Design 74(4): 358-368 (Journal)
- Registered Authors
- Tsang, Michael
- angiogenesis, high-content screening, multi-drug resistance, pironetin, zebrafish
- MeSH Terms
- Angiogenesis Inhibitors/chemical synthesis
- Angiogenesis Inhibitors/chemistry*
- Angiogenesis Inhibitors/pharmacology
- CHO Cells
- Cell Line, Tumor
- Drug Resistance, Neoplasm
- Drug Screening Assays, Antitumor
- Mitosis/drug effects
- Neovascularization, Physiologic/drug effects*
- Pyrones/chemical synthesis
- Tubulin Modulators/chemical synthesis
- Tubulin Modulators/chemistry*
- Tubulin Modulators/pharmacology
- 19691472 Full text @ Chem. Biol. Drug Des.
Vogt, A., McPherson, P.A., Shen, X., Balachandran, R., Zhu, G., Raccor, B.S., Nelson, S.G., Tsang, M., and Day, B.W. (2009) High-Content Analysis of Cancer-Cell-Specific Apoptosis and Inhibition of in Vivo Angiogenesis by Synthetic (-)-Pironetin and Analogs. Chemical Biology & Drug Design. 74(4):358-368.
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.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes