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  Total Synthesis of Iejimalide A-D and Assessment of the Remarkable Actin-Depolymerizing Capacity of These Polyene Macrolides

Fürstner, A., Nevado, C., Waser, M., Tremblay, M., Chevrier, C., Teplý, F., et al. (2007). Total Synthesis of Iejimalide A-D and Assessment of the Remarkable Actin-Depolymerizing Capacity of These Polyene Macrolides. Journal of the American Chemical Society, 129(29), 9150-9161. doi:10.1021/ja072334v.

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Fürstner, Alois1, Author           
Nevado, Cristina1, Author           
Waser, Mario1, Author           
Tremblay, Martin1, Author           
Chevrier, Carine1, Author           
Teplý, Filip1, Author           
Aïssa, Christophe1, Author           
Moulin, Emilie1, Author           
Müller, Oliver2, Author
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1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              
2Max-Planck-Institut für Molekulare Physiologie, D-44227 Dortmund, Germany , ou_persistent22              

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 Abstract: A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalide A−D (1−4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclization precursor containing no less than 10 double bonds. Because of the exceptional sensitivity of this polyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming, the assembly process hinged upon the judicious choice of protecting groups and the careful optimization of all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzuki reactions of elaborate coupling partners have been developed that hold considerable promise for applications in other complex settings. Moreover, a series of non-natural “iejimalide-like” compounds has been prepared, differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aid of these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues on the actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculins which constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are thereby well accommodated, without compromising the biological effects. The iejimalides hence constitute an important new class of probe molecules for chemical biology in addition to their role as promising lead structures for the development of novel anticancer agents.

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Language(s): eng - English
 Dates: 2007-04-032007-06-292007-07-25
 Publication Status: Published in print
 Pages: 12
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 336958
DOI: 10.1021/ja072334v
ISI: 000248185500046
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Title: Journal of the American Chemical Society
  Other : J. Am. Chem. Soc.
  Abbreviation : JACS
Source Genre: Journal
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Publ. Info: Washington, DC : American Chemical Society
Pages: - Volume / Issue: 129 (29) Sequence Number: - Start / End Page: 9150 - 9161 Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870