Making epothilones fluoresce: design, synthesis, and biological characterization of a fluorescent N12-aza-epothilone (azathilone)

Gertsch, Jürg; Feyen, Fabian; Bützberger, Alexander; Gerber, Barbara; Pfeiffer, Bernhard; Altmann, Karl-Heinz (2009). Making epothilones fluoresce: design, synthesis, and biological characterization of a fluorescent N12-aza-epothilone (azathilone). ChemBioChem, 10(15), pp. 2513-21. Weinheim: Wiley-VCH 10.1002/cbic.200900376

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Gertsch, Jürg

ISSN:

1439-4227

Publisher:

Wiley-VCH

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 15:12

Last Modified:

04 May 2014 23:23

Publisher DOI:

10.1002/cbic.200900376

PubMed ID:

19760690

Web of Science ID:

000271095600013

URI:

https://boris.unibe.ch/id/eprint/31626 (FactScience: 196257)

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