title: 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.affiliation: Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15260, USA. avogt@pitt.edu
authors.forename: Andreas
authors.initials: A
authors.lastname: Vogt
authors.forename: Peter A
authors.initials: PA
authors.lastname: McPherson
authors.forename: Xiaoqiang
authors.initials: X
authors.lastname: Shen
authors.forename: Raghavan
authors.initials: R
authors.lastname: Balachandran
authors.forename: Guangyu
authors.initials: G
authors.lastname: Zhu
authors.forename: Brianne S
authors.initials: BS
authors.lastname: Raccor
authors.forename: Scott G
authors.initials: SG
authors.lastname: Nelson
authors.forename: Michael
authors.initials: M
authors.lastname: Tsang
authors.forename: Billy W
authors.initials: BW
authors.lastname: Day
mesh_terms: D020533:Angiogenesis Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000187:drug effects; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011753:Pyrones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015027:Zebrafish
chemical_list: D020533:Angiogenesis Inhibitors; D011753:Pyrones; D050257:Tubulin Modulators; C088446:pironetin
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