| Making epothilones fluoresce: design, synthesis, and biological characterization of a fluorescent N12-aza-epothilone (azathilone). | |
| | |
MedLine Citation:
|
PMID: 19760690 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
|
A green fluorescent 12-aza-epothilone (azathilone) derivative has been prepared through the attachment of the 4-nitro-2,1,3-benzoxadiazole (NBD) fluorophore to the 12-nitrogen atom of the azamacrolide core structure. While less potent than natural epothilones or different N12-acylated azathilone derivatives, NBD-azathilone (3) promotes tubulin assembly, inhibits cancer cell proliferation in vitro and arrests the cell cycle at the G2/M transition. Most significantly, the binding of 3 to cellular microtubules (MTs) could be directly visualized by confocal fluorescence microscopy. Based on competition binding experiments with laulimalide-stabilized MTs in vitro, the N12-Boc substituted azathilone 1, Epo A, and NBD-azathilone (3) all interact with the same tubulin-binding site. Computational studies provided a structural model of the complexes between beta-tubulin and 1 or 3, respectively, in which the NBD moiety of 3 or the BOC moiety of 1 directly and specifically contribute to MT binding. Collectively, these data demonstrate that the cellular effects of 3 and, by inference, also of other azathilones are the result of their interactions with the cellular MT network. |
| | |
Authors:
|
J?rg Gertsch; Fabian Feyen; Alexander B?tzberger; Barbara Gerber; Bernhard Pfeiffer; Karl-Heinz Altmann |
Publication Detail:
|
Type: Journal Article; Research Support, Non-U.S. Gov't |
Journal Detail:
|
Title: Chembiochem : a European journal of chemical biology Volume: 10 ISSN: 1439-7633 ISO Abbreviation: Chembiochem Publication Date: 2009 Oct |
Date Detail:
|
Created Date: 2009-10-14 Completed Date: 2010-02-17 Revised Date: - |
Medline Journal Info:
|
Nlm Unique ID: 100937360 Medline TA: Chembiochem Country: Germany |
Other Details:
|
Languages: eng Pagination: 2513-21 Citation Subset: IM |
Affiliation:
|
Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, Swiss Federal Institute of Technology (ETH) Z?rich, HCI H405, Wolfgang-Pauli-Strasse 10, 8093 Z?rich, Switzerland. |
Export Citation:
|
APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
|
4-Chloro-7-nitrobenzofurazan
/
analogs & derivatives*,
chemical synthesis,
chemistry,
metabolism,
pharmacology Binding Sites Cell Cycle / drug effects Cell Line, Tumor Cell Proliferation / drug effects Drug Design* Epothilones / chemical synthesis, chemistry*, metabolism*, pharmacology Fluorescence Fluorescent Dyes / chemical synthesis*, chemistry, metabolism*, pharmacology Humans Microtubules / metabolism Spectrum Analysis Tubulin / metabolism |
| Chemical | |
Reg. No./Substance:
|
0/10,14-dihydroxy-9,11,13,13-tetramethyl-2-(1-methyl-2-(2-methyl-thiazol-4-yl)-vinyl)-5-(7-nitro-benzo(1,2,5)oxadiazol-4-yl)-1-oxa-5-aza-cyclohexadecane-12,16-dione; 0/Epothilones; 0/Fluorescent Dyes; 0/Tubulin; 10199-89-0/4-Chloro-7-nitrobenzofurazan |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
Previous Document: Epidemiologic features and clinical subgroups of anotia/microtia in Texas.
Next Document: Phosphatidylethanolamine-binding proteins, including RKIP, exhibit affinity for phosphodiesterase-5 ...