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Synthesis and evaluation of duocarmycin and CC-1065 analogues incorporating the 1,2,9,9a-tetrahydrocyclopropa c benz e -3-azaindol-4-one (CBA) alkylation subunit

Academic Article
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Overview

related to degree

  • Kastrinsky, David, Ph.D. in Synthetic Organic Chemistry, Scripps Research 2000 - 2005

authors

  • Parrish, J. P.
  • Kastrinsky, David
  • Hwang, I.
  • Boger, Dale

publication date

  • November 2003

journal

  • Journal of Organic Chemistry  Journal

abstract

  • An efficient eight-step synthesis (53% overall) and the evaluation of 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]-3-azaindol-4-one (CBA) and its derivatives containing an aza variant of the CC-1065/duocarmycin alkylation subunit are detailed. This unique deep-seated aza modification provided an unprecedented 2-aza-4,4-spirocyclopropacyclohexadienone that was characterized chemically and structurally (X-ray). CBA proved structurally identical with CBI, the carbon analogue, including the stereoelectronic alignment of the key cyclopropane, its bond lengths, and the bond length of the diagnostic C3a-N2 bond, reflecting the extent of vinylogous amide (amidine) conjugation. Despite these structural similarities, CBA and its derivatives were found to be much more reactive toward solvolysis and hydrolysis, much less effective DNA alkylating agents (1000-fold), and biologically much less potent (100- to 1000-fold) than the corresponding CBI derivatives.

subject areas

  • Alkylation
  • Crystallography, X-Ray
  • Cyclopropanes
  • Indoles
  • Molecular Structure
  • Pyrrolidinones
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Identity

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/jo035119f

PubMed ID

  • 14604371
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Additional Document Info

start page

  • 8984

end page

  • 8990

volume

  • 68

issue

  • 23

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