Scripps VIVO scripps research logo

  • Index
  • Log in
  • Home
  • People
  • Organizations
  • Research
  • Events
Search form

A novel class of CC-1065 and duocarmycin analogues subject to mitomycin-related reductive activation

Academic Article
uri icon
  • Overview
  • Identity
  • Additional Document Info
  • View All
scroll to property group menus

Overview

related to degree

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

authors

  • Boger, Dale
  • Garbaccio, Robert

publication date

  • October 1999

journal

  • Journal of Organic Chemistry  Journal

abstract

  • A new class of DNA alkylating agents is described that incorporate the quinone of the mitomycins, which is thought to impart tumor cell selectivity as a result of preferential reduction and activation in hypoxic tumors, into the AT-selective binding framework of the duocarmycins capable of mitomycin-like reductive activation and duocarmycin-like spirocyclization and subsequent DNA alkylation. Consistent with this design, the quinone prodrugs fail to alkylate DNA unless reductively activated and then do so with an adenine N3 alkylation sequence selectivity identical to that of the duocarmycins. Additionally, the agents exhibit a selectivity toward DT-Diaphorase (NQO1)-containing versus DT-Diaphorase-deficient (resistant) tumor cell lines, and they were shown to be effective substrates for reduction by recombinant human DT-Diaphorase. As such, the agents constitute effective duocarmycin and CC-1065 analogues subject to reductive activation. In addition, the solvolysis pH rate dependence of a series of reactive spirocyclopropanes revealed a unique and inverted order of reactivity at pH 7 versus pH 3. This behavior and the structural features responsible for it are consistent with an acid-catalyzed reaction at pH 3, but a direct uncatalyzed S(N)2 reaction at pH 7 that is not subject to acid catalysis.
scroll to property group menus

Identity

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/jo991301y

PubMed ID

  • 11674758
scroll to property group menus

Additional Document Info

start page

  • 8350

end page

  • 8362

volume

  • 64

issue

  • 22

©2021 The Scripps Research Institute | Terms of Use | Powered by VIVO

  • About
  • Contact Us
  • Support