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Are the duocarmycin and CC-1065 DNA alkylation reactions acid-catalyzed? Solvolysis pH-rate profiles suggest they are not

Academic Article
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Overview

related to degree

  • Garbaccio, Robert, Ph.D. in Chemistry, Scripps Research 1994 - 1999

authors

  • Boger, Dale
  • Garbaccio, Robert

publication date

  • July 1999

journal

  • Journal of Organic Chemistry  Journal

abstract

  • A study of the solvolysis pH-rate profiles for two key reactive CC-1065/duocarmycin alkylation subunit analogues is detailed. Unlike the authentic alkylation subunits and N-BOC-CBI (4) which are too stable to establish complete solvolysis pH-rate profiles, the analogues N-BOC-CBQ (5) and N-BOC-CNA (6) are reactive throughout the pH range of 2-12. Moreover, they possess progressively diminished vinylogous amide conjugation resulting in a corresponding progressively increasing reactivity adopting and reflecting conformations analogous to that proposed for DNA-bound CC-1065. For both, the acid-catalyzed reaction was observed only at the lower pH of 2-5, and the uncatalyzed solvolysis reaction rate dominated at pH >/=6, indicating that the CC-1065 and duocarmycin DNA alkylation reaction observed at pH 7.4 need not be an acid-catalyzed reaction. The studies provide further strong evidence that catalysis for the DNA alkylation reaction (pH 7.4) is derived from a DNA binding-induced conformational change in the agents that disrupts the stabilizing alkylation subunit vinylogous amide conjugation activating the agents for nucleophilic attack independent of pH.
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Identity

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/jo990762g

PubMed ID

  • 11674637
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Additional Document Info

start page

  • 5666

end page

  • 5669

volume

  • 64

issue

  • 15

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