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Synthesis and biological activity of 7,8,9-trideoxy- and 7R desTHP-peloruside A.

Abstract
The stereoselective syntheses of 7,8,9-trideoxypeloruside A (4) and a monocyclic peloruside A analogue lacking the entire tetrahydropyran moiety (3) are described. The syntheses proceeded through the PMB-ether of an ω-hydroxy β-keto aldehyde as a common intermediate which was elaborated into a pair of diastereomeric 1,3-syn and -anti diols by stereoselective Duthaler-Hafner allylations and subsequent 1,3-syn or anti reduction. One of these isomers was further converted into a tetrahydropyran derivative in a high-yielding Prins reaction, to provide the precursor for bicyclic analogue 4. Downstream steps for both syntheses included the substrate-controlled addition of a vinyl lithium intermediate to an aldehyde, thus connecting the peloruside side chain to C15 (C13) of the macrocyclic core structure in a fully stereoselective fashion. In the case of monocyclic 3 macrocyclization was based on ring-closing olefin metathesis (RCM), while bicyclic 4 was cyclized through Yamaguchi-type macrolactonization. The macrolactonization step was surprisingly difficult and was accompanied by extensive cyclic dimer formation. Peloruside A analogues 3 and 4 inhibited the proliferation of human cancer cell lines in vitro with micromolar and sub-micromolar IC50 values, respectively. The higher potency of 4 highlights the importance of the bicyclic core structure of peloruside A for nM biological activity.
AuthorsChristoph W Wullschleger, Jürg Gertsch, Karl-Heinz Altmann
JournalChemistry (Weinheim an der Bergstrasse, Germany) (Chemistry) Vol. 19 Issue 39 Pg. 13105-11 (Sep 23 2013) ISSN: 1521-3765 [Electronic] Germany
PMID24038407 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Chemical References
  • Antineoplastic Agents
  • Biological Factors
  • Bridged Bicyclo Compounds, Heterocyclic
  • Lactones
  • peloruside A
Topics
  • Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
  • Biological Factors (chemistry, metabolism)
  • Bridged Bicyclo Compounds, Heterocyclic (chemical synthesis, chemistry, metabolism, pharmacology)
  • Cell Line, Tumor
  • Cell Proliferation
  • Cyclization
  • Humans
  • Inhibitory Concentration 50
  • Lactones (chemical synthesis, chemistry, metabolism, pharmacology)
  • Stereoisomerism

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