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  Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics

Micoine, K., Persich, P., Llaveria Cros, J., Lam, M.-H., Maderna, A., Loganzo, F., et al. (2013). Total Syntheses and Biological Reassessment of Lactimidomycin, Isomigrastatin and Congener Glutarimide Antibiotics. Chemistry – A European Journal, 19(23), 7370-7383. doi:10.1002/chem.201300393.

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2013
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Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim
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 Creators:
Micoine, Kevin1, Author              
Persich, Peter1, Author              
Llaveria Cros, Josep1, Author              
Lam, My-Hanh2, Author
Maderna, Andreas3, Author
Loganzo, Frank2, Author
Fürstner, Alois1, Author              
Affiliations:
1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              
2Pfizer Oncology, 401 N. Middletown Road Pearl River, NY, 10965 (USA), ou_persistent22              
3Pfizer Oncology Medicinal Chemistry, 445 Eastern Point Road Groton, CT 06340 (USA), ou_persistent22              

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Free keywords: cell migration inhibition · cytotoxicity · metathesis · natural products · total synthesis
 Abstract: Lactimidomycin (1) was described in the literature as an exquisitely potent cell migration inhibitor. Encouraged by this claim, we developed a concise and scalable synthesis of this bipartite glutarimide-macrolide antibiotic, which relies on the power of ring-closing alkyne metathesis (RCAM) for the formation of the unusually strained 12-membered head group. Subsequent deliberate digression from the successful path to 1 also brought the sister compound isomigrastatin (2) as well as a series of non-natural analogues of these macrolides into reach. A careful biological re-evaluation of this compound collection showed 1 and progeny to be potently cytotoxic against a panel of cancer cell lines, even after one day of compound exposure; therefore any potentially specific effects on tumor cell migration were indistinguishable from the acute effect of cell death. No significant cell migration inhibition was observed at sub-toxic doses. Although these findings cannot be reconciled with some reports in the literature, they are in accord with the notion that lactimidomycin is primarily a ribosome-binder able to effectively halt protein biosynthesis at the translation stage.

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Language(s): eng - English
 Dates: 2013-04-172013-06-03
 Publication Status: Published in print
 Pages: 14
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1002/chem.201300393
 Degree: -

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Title: Chemistry – A European Journal
  Other : Chem. – Eur. J.
  Other : Chem. Eur. J.
Source Genre: Journal
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Publ. Info: Weinheim, Germany : VCH Verlagsgesellschaft
Pages: 14 Volume / Issue: 19 (23) Sequence Number: - Start / End Page: 7370 - 7383 Identifier: ISSN: 0947-6539
CoNE: https://pure.mpg.de/cone/journals/resource/954926979058