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Synthesis and evaluation of N-aryl and N-alkenyl CBI derivatives

Academic Article
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Overview

related to degree

  • Trzupek, John, Ph.D. in Chemistry, Scripps Research 2001 - 2006

authors

  • Parrish, J. P.
  • Trzupek, John
  • Hughes, T. V.
  • Hwang, I.
  • Boger, Dale

publication date

  • November 2004

journal

  • Bioorganic & Medicinal Chemistry  Journal

abstract

  • The preparation of a novel series of N-aryl CBI derivatives in which an aryl substituent could be used to predictably modulate the reactivity of the resulting CC-1065/duocarmycin alkylation subunit analogue is detailed and its extension to a unique series of N-alkenyl derivatives is reported. The N-aryl derivatives were found to be exceptionally stable and to exhibit well-defined relationships between structure (X-ray), reactivity, and cytotoxic potency. When combined with the results of past investigations, the studies define a fundamental parabolic relationship between reactivity and cytotoxic potency. The parabolic relationship establishes that compounds in the series should possess sufficient stability to reach their biological target (DNA), yet maintain sufficient reactivity to effectively alkylate DNA upon reaching the biological target. Just as importantly, it defined this optimal balance of stability and reactivity that may be used for future design of related analogues. Notably, the duocarmycin SA and yatakemycin alkylation subunit lies at this optimal stability/reactivity position, whereas the CC-1065 and duocarmycin A alkylation subunits lie progressively and significantly to the left of this optimal position (too reactive).

subject areas

  • Alkylating Agents
  • Base Sequence
  • Crystallography, X-Ray
  • DNA
  • Drug Evaluation, Preclinical
  • Indoles
  • Pyrrolidinones
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Research

keywords

  • CC-1065
  • antitumor
  • duocarmycins
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Identity

International Standard Serial Number (ISSN)

  • 0968-0896

Digital Object Identifier (DOI)

  • 10.1016/j.bmc.2004.08.032

PubMed ID

  • 15498660
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Additional Document Info

start page

  • 5845

end page

  • 5856

volume

  • 12

issue

  • 22

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