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  Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide

Mailhol, D., Willwacher, J., Kausch-Busies, N., Rubitski, E. E., Sobol, Z., Schuler, M., et al. (2014). Synthesis, Molecular Editing, and Biological Assessment of the Potent Cytotoxin Leiodermatolide. Journal of the American Chemical Society, 136(44), 15719-15729. doi:10.1021/ja508846g.

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 Creators:
Mailhol, Damien1, Author              
Willwacher, Jens1, Author              
Kausch-Busies, Nina1, Author              
Rubitski, Elizabeith E.2, Author
Sobol, Zhanna2, Author
Schuler, Maik2, Author
Lam, My-Hanh3, Author
Musto, Sylvia3, Author
Loganzo, Frank3, Author
Maderna, Andreas4, Author
Fürstner, Alois1, Author              
Affiliations:
1Research Department Fürstner, Max-Planck-Institut für Kohlenforschung, Max Planck Society, ou_1445584              
2Pfizer Drug Safety Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, United States, ou_persistent22              
3Pfizer Oncology, 401 North Middletown Road, Pearl River, New York 10965, United States, ou_persistent22              
4Pfizer Oncology Medicinal Chemistry, 445 Eastern Point Road, Groton, Connecticut 06340, United States, ou_persistent22              

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 Abstract: It was by way of total synthesis that the issues concerning the stereostructure of leiodermatolide (1) have recently been solved; with the target now being unambiguously defined, the mission of synthesis changes as to secure a meaningful supply of this exceedingly scarce natural product derived from a deep-sea sponge. To this end, a scalable route of 19 steps (longest linear sequence) has been developed, which features a catalytic asymmetric propargylation of a highly enolizable β-keto-lactone, a ring closing alkyne metathesis and a modified Stille coupling as the key transformations. Deliberate digression from this robust blueprint brought a first set of analogues into reach, which allowed the lead qualities of 1 to be assessed. The acquired biodata show that 1 is a potent cytotoxin in human tumor cell proliferation assays, distinguished by GI50 values in the ≤3 nM range even for cell lines expressing the Pgp efflux transporter. Studies with human U2OS cells revealed that 1 causes mitotic arrest, micronucleus induction, centrosome amplification and tubulin disruption, even though no evidence for direct tubulin binding has been found in cell-free assays; moreover, the compound does not seem to act through kinase inhibition. Indirect evidence points at centrosome declustering as a possible mechanism of action, which provides a potentially rewarding outlook in that centrosome declustering agents hold promise of being inherently selective for malignant over healthy human tissue.

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Language(s): eng - English
 Dates: 2014-08-272014-10-272014-11-05
 Publication Status: Published in print
 Pages: 11
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1021/ja508846g
 Degree: -

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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: American Chemical Society
Pages: 11 Volume / Issue: 136 (44) Sequence Number: - Start / End Page: 15719 - 15729 Identifier: ISSN: 0002-7863
CoNE: https://pure.mpg.de/cone/journals/resource/954925376870