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Synthesis and biological properties of novel brefeldin a analogues

New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) w...

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Main Authors: Seehafer, Kai (Author) , Rominger, Frank (Author) , Helmchen, Günter (Author) , Langhans, Markus (Author) , Robinson, David G. (Author) , Özata, Başak (Author) , Brügger, Britta (Author) , Klein, Christian D. (Author)
Format: Article (Journal)
Language:English
Published: June 27, 2013
In: Journal of medicinal chemistry
Year: 2013, Volume: 56, Issue: 14, Pages: 5872-5884
ISSN:1520-4804
DOI:10.1021/jm400615g
Online Access:Verlag, Volltext: http://dx.doi.org/10.1021/jm400615g
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Author Notes:Kai Seehafer, Frank Rominger, Günter Helmchen, Markus Langhans, David G.Robinson, Başak Özata, Britta Brügger, Jeroen R.P.M. Strating, Frank J.M. van Kuppeveld, and Christian D.Klein
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Summary:New brefeldin A (1) analogues were obtained by introducing a variety of substituents at C15. Most of the analogues exhibited significant biological activity. (15R)-Trifluoromethyl-nor-brefeldin A (3), (15R)-vinyl-nor-brefeldin A (5), their epimers 4 and 6 as well as (15S)-ethyl-nor-brefeldin A (2) were prepared from the key building blocks 12 or 24 by Julia-Kocienski olefination with tetrazolyl sulfones and subsequent macrolactonization. The vinyl derivative 5 allowed analogues to be synthesized by hydroboration and Suzuki-Miyaura coupling. The following biological properties were assessed: (a) inhibition of cell growth of human cancer cells (NCI), (b) induction of morphological changes of the Golgi apparatus of plant and mammalian cells, and (c) influence on the replication of the enterovirus CVB3. Furthermore, conformational aspects were studied by X-ray crystal structure analysis and molecular mechanics calculations, including docking of the analogues into the brefeldin A binding site of an Arf1/Sec7-complex.
Item Description:Gesehen am 11.05.2017
Physical Description:Online Resource
ISSN:1520-4804
DOI:10.1021/jm400615g

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