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A remarkable series of vinblastine analogues displaying enhanced activity and an unprecedented tubulin binding steric tolerance: C20' urea derivatives

Academic Article
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Overview

related to degree

  • Duncan, Katharine, Ph.D. in Chemistry, Scripps Research 2008 - 2014

authors

  • Leggans, E. K.
  • Duncan, Katharine
  • Barker, T. J.
  • Schleicher, K. D.
  • Boger, Dale

publication date

  • February 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • A systematic series of previously inaccessible key C20' urea and thiourea derivatives of vinblastine were prepared from 20'-aminovinblastine that was made accessible through a unique Fe(III)/NaBH(4)-mediated alkene functionalization reaction of anhydrovinblastine. Their examination defined key structural features of the urea-based analogues that contribute to their properties and provided derivatives that match or exceed the potency of vinblastine by as much as 10-fold in cell-based functional assays, which is directly related to their relative tubulin binding affinity. In contrast to expectations based on apparent steric constraints of the tubulin binding site surrounding the vinblastine C20' center depicted in an X-ray cocrystal structure, remarkably large C20' urea derivatives are accommodated.

subject areas

  • Animals
  • Antineoplastic Agents, Phytogenic
  • Cell Division
  • Drug Screening Assays, Antitumor
  • Leukemia, Experimental
  • Mice
  • Models, Molecular
  • Protein Binding
  • Spectrometry, Mass, Electrospray Ionization
  • Spectrophotometry, Infrared
  • Tubulin
  • Urea
  • Vinblastine
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Identity

PubMed Central ID

  • PMC3574233

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm3015684

PubMed ID

  • 23244701
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Additional Document Info

start page

  • 628

end page

  • 639

volume

  • 56

issue

  • 3

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