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  Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors

Brohm, D., Philippe, N., Metzger, S., Bhargava, A., Müller, O., Lieb, F., et al. (2002). Solid-phase synthesis of dysidiolide-derived protein phosphatase inhibitors. Journal of the American Chemical Society, 124(44): 1, pp. 13171-13178. Retrieved from http://dx.doi.org/10.1021/ja027609f.

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Genre: Journal Article
Alternative Title : J. Am. Chem. Soc.

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 Creators:
Brohm, Dirk1, Author
Philippe, Nicolas, Author
Metzger, Susanne, Author
Bhargava, Ajay, Author
Müller, Oliver2, Author              
Lieb, Folker, Author
Waldmann, Herbert3, Author              
Affiliations:
1Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753286              
2Sonstige Wissenschaftliche Organisationseinheiten, Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753294              
3Abt. IV: Chemische Biologie, Max Planck Institute of Molecular Physiology, Max Planck Society, ou_1753290              

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 Abstract: Biologically active natural products can be regarded as evolutionary selected and biologically validated starting points in structural space for the development of compound libraries. For libraries designed and synthesized around a given natural product, a higher hit rate and the identification of biologically relevant hits can be expected, justifying a probably higher investment in the development of the corresponding syntheses. This approach requires the development of complex multistep reaction sequences on the solid phase. Employing the protein phosphatase Cdc25 inhibitor dysidiolide as an example, we demonstrate that this goal can be achieved successfully. The reaction sequences developed led to dysidiolide analogues in overall 8-12 linear steps with the longest sequence on the solid support amounting to up to 11 sequential transformations. The desired products were obtained in overall yields ranging from 6% to 27% and in multimilligram amounts starting from 100 mg of resin. The transformations applied include a variety of very different reaction types widely used in organic synthesis (i.e., an asymmetric cycloaddition employing a removable chiral auxiliary, different organometallic transformations, olefination reactions, different oxidation reactions, acidic hydrolyses, and a nucleophilic substitution). Biological investigation of the eight dysidiolide analogues synthesized showed that they inhibit Cdc25C in the low micromolar range with the IC50 value varying by a factor of 20 and that they display considerable and differing biological activities in cytotoxicity assays employing different cancer cell lines.

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Language(s): eng - English
 Dates: 2002-11-01
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: eDoc: 14646
URI: http://dx.doi.org/10.1021/ja027609f
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Title: Journal of the American Chemical Society
  Alternative Title : J. Am. Chem. Soc.
Source Genre: Journal
 Creator(s):
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Publ. Info: -
Pages: - Volume / Issue: 124 (44) Sequence Number: 1 Start / End Page: 13171 - 13178 Identifier: -