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A fundamental relationship between hydrophobic properties and biological activity for the duocarmycin class of DNA-alkylating antitumor drugs: hydrophobic-binding-driven bonding

Academic Article
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Overview

related to degree

  • Duncan, Katharine, Ph.D. in Chemistry, Scripps Research 2008 - 2014
  • Wolfe, Amanda, Ph.D. in Chemistry, Scripps Research 2008 - 2013
  • Lajiness, James, Ph.D. in Organic Chemistry, Scripps Research 2007 - 2012

authors

  • Wolfe, Amanda
  • Duncan, Katharine
  • Lajiness, James
  • Zhu, K. C.
  • Duerfeldt, A. S.
  • Boger, Dale

publication date

  • September 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • Two systematic series of increasingly hydrophilic derivatives of duocarmycin SA that feature the incorporation of ethylene glycol units (n = 1-5) into the methoxy substituents of the trimethoxyindole subunit are described. These derivatives exhibit progressively increasing water solubility along with progressive decreases in cell growth inhibitory activity and DNA alkylation efficiency with the incremental ethylene glycol unit incorporations. Linear relationships of cLogP with -log IC50 for cell growth inhibition and -log AE (AE = cell-free DNA alkylation efficiency) were observed, with the cLogP values spanning the productive range of 2.5-0.49 and the -log IC50 values spanning the range of 11.2-6.4, representing IC50 values that vary by a factor of 10(5) (0.008 to 370 nM). The results quantify the fundamental role played by the hydrophobic character of the compound in the expression of the biological activity of members in this class (driving the intrinsically reversible DNA alkylation reaction) and define the stunning magnitude of its effect.

subject areas

  • Animals
  • Antineoplastic Agents, Alkylating
  • Binding Sites
  • Cell Line, Tumor
  • DNA
  • Hydrophobic and Hydrophilic Interactions
  • Indoles
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Mice
  • Pyrroles
  • Solubility
  • Spectrometry, Mass, Electrospray Ionization
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Identity

PubMed Central ID

  • PMC3793852

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm400665c

PubMed ID

  • 23944748
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Additional Document Info

start page

  • 6845

end page

  • 6857

volume

  • 56

issue

  • 17

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