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Total synthesis and evaluation of a key series of C5-substituted vinblastine derivatives

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Overview

authors

  • Va, Porino Jinjo
  • Campbell, E. L.
  • Robertson, W. M.
  • Boger, Dale

publication date

  • June 2010

journal

  • Journal of the American Chemical Society  Journal

abstract

  • A remarkably concise seven- to eight-step total synthesis of a systematic series of key vinblastine derivatives is detailed and used to characterize the importance and probe the role of the C5 ethyl substituent (R = H, Me, Pr, CH=CH(2), C[triple bond]CH, CH(2)OH, and CHO vs Et). The analogues, which bear deep-seated structural changes accessible only by total synthesis, were prepared using a powerful intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of 1,3,4-oxadiazoles ideally suited for use in the assemblage of the vindoline-derived lower subunit followed by their incorporation into the vinblastine analogues through the use of a single-step biomimetic coupling with catharanthine. The evaluation of the series revealed that the tubulin binding site surrounding this C5 substituent is exquisitely sensitive to the presence (Et > H, 10-fold), size (Me < or = Et > Pr, 10-fold), shape (Et > CH=CH(2) and C[triple bond]CH, > 4-fold), and polarity (Et > CHO > CH(2)OH, >10-20-fold) of this substituent and that on selected occasions only a C5 methyl group may provide analogues that approach the activity observed with the naturally occurring C5 ethyl group.

subject areas

  • Antineoplastic Agents
  • Cell Line, Tumor
  • Humans
  • Inhibitory Concentration 50
  • Models, Molecular
  • Molecular Conformation
  • Tubulin
  • Vinblastine
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Identity

PubMed Central ID

  • PMC2903230

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja1027748

PubMed ID

  • 20518465
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Additional Document Info

start page

  • 8489

end page

  • 8495

volume

  • 132

issue

  • 24

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