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Issue 31, 2019
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Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity

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Abstract

The 2-(silyloxymethyl)allylboration of aldehydes was established to enable stereoselective access to α-(exo)-methylene γ-butyrolactones under mild conditions. Acid-labile functionality and chiral carbonyl compounds are tolerated. Excellent asymmetric induction was observed for β,β′-disubstituted α,β-epoxy aldehydes. These findings led to the enantioselective total synthesis of the sesquiterpene natural product (−)-parthenolide, its unnatural (+)-enantiomer, and diastereoisomers. Among all the isomers tested in cell culture, only (−)-parthenolide showed potent inhibition of microtubule detyrosination in living cells, confirming its exquisite selectivity on tubulin carboxypeptidase activity. On the other hand, the anti-inflammatory activity of the parthenolides was weaker and less selective with regard to compound stereochemistry.

Graphical abstract: Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity

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Publication details

The article was received on 25 Mar 2019, accepted on 14 Jun 2019 and first published on 26 Jun 2019


Article type: Edge Article
DOI: 10.1039/C9SC01473J
Chem. Sci., 2019,10, 7358-7364
  • Open access: Creative Commons BY-NC license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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    Stereoselective total synthesis of parthenolides indicates target selectivity for tubulin carboxypeptidase activity

    R. R. A. Freund, P. Gobrecht, Z. Rao, J. Gerstmeier, R. Schlosser, H. Görls, O. Werz, D. Fischer and H. Arndt, Chem. Sci., 2019, 10, 7358
    DOI: 10.1039/C9SC01473J

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