Golgi-modifying properties of macfarlandin E and the synthesis and evaluation of its 2,7-dioxabicyclo[3.2.1]octan-3-one core
- 23 March 2010
- journal article
- Published by Proceedings of the National Academy of Sciences in Proceedings of the National Academy of Sciences of the United States of America
- Vol. 107 (14), 6158-6163
- https://doi.org/10.1073/pnas.1001421107
Abstract
Golgi-modifying properties of the spongian diterpene macfarlandin E (MacE) and a synthetic analog, t-Bu-MacE, containing its 2,7-dioxabicyclo[3.2.1]octan-3-one moiety are reported. Natural product screening efforts identified MacE as inducing a novel morphological change in Golgi structure defined by ribbon fragmentation with maintenance of the resulting Golgi fragments in the pericentriolar region. t-Bu-MacE, which possesses the substituted 2,7-dioxabicyclo[3.2.1]octan-3-one but contains a tert-butyl group in place of the hydroazulene subunit of MacE, was prepared by chemical synthesis. Examination of the Golgi-modifying properties of MacE, t-Bu-MacE, and several related structures revealed that the entire oxygen-rich bridged-bicyclic fragment is required for induction of this unique Golgi organization phenotype. Further characterization of MacE-induced Golgi modification showed that protein secretion is inhibited, with no effect on the actin or microtubule cytoskeleton being observed. The conversion of t-Bu-MacE and a structurally related des-acetoxy congener to substituted pyrroles in the presence of primary amines in protic solvent at ambient temperatures suggests that covalent modification might be involved in the Golgi-altering activity of MacE.Keywords
This publication has 39 references indexed in Scilit:
- A Primary Role for Golgi Positioning in Directed Secretion, Cell Polarity, and Wound HealingMolecular Biology of the Cell, 2009
- Trifunctional norrisolide probes for the study of Golgi vesiculationBioorganic & Medicinal Chemistry Letters, 2007
- Synthesis of a 10,000-Membered Library of Molecules Resembling Carpanone and Discovery of Vesicular Traffic InhibitorsJournal of the American Chemical Society, 2006
- Michael, Michael–aldol and Michael–Michael reactions of enolate equivalents of butane-2,3-diacetal protected glycolic acid derivativesOrganic & Biomolecular Chemistry, 2005
- Structural snapshots of the mechanism and inhibition of a guanine nucleotide exchange factorNature, 2003
- Gβγ-Mediated Regulation of Golgi Organization Is through the Direct Activation of Protein Kinase DCell, 1999
- Golgi dispersal during microtubule disruption: regeneration of Golgi stacks at peripheral endoplasmic reticulum exit sites.Molecular Biology of the Cell, 1996
- Brefeldin A: insights into the control of membrane traffic and organelle structure.The Journal of cell biology, 1992
- Ten new rearranged spongian diterpenes from two Dysidea speciesThe Journal of Organic Chemistry, 1988
- Three new rearranged spongian diterpenes from chromodoris macfarland: reappraisal of the structures of dendrillolides A and BThe Journal of Organic Chemistry, 1986