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Rational design, synthesis, and evaluation of key analogues of CC-1065 and the duocarmycins

Academic Article
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Overview

related to degree

  • Macmillan, Karen Smith, Ph.D. in Chemistry, Scripps Research 2004 - 2009
  • Tichenor, Mark, Ph.D. in Chemistry, Scripps Research 2002 - 2007
  • Wolkenberg, Scott, Ph.D. in Chemistry, Scripps Research 1998 - 2003

authors

  • Tichenor, Mark
  • Macmillan, Karen Smith
  • Stover, J. S.
  • Wolkenberg, Scott
  • Pavani, M. G.
  • Zanella, L.
  • Zaid, A. N.
  • Spalluto, G.
  • Rayl, T. J.
  • Hwang, I.
  • Baraldi, P. G.
  • Boger, Dale

publication date

  • November 2007

journal

  • Journal of the American Chemical Society  Journal

abstract

  • The design, synthesis, and evaluation of a predictably more potent analogue of CC-1065 entailing the substitution replacement of a single skeleton atom in the alkylation subunit are disclosed and were conducted on the basis of design principles that emerged from a fundamental parabolic relationship between chemical reactivity and cytotoxic potency. Consistent with projections, the 7-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[3,2-e]indol-4-one (MeCTI) alkylation subunit and its isomer 6-methyl-1,2,8,8a-tetrahydrocyclopropa[c]thieno[2,3-e]indol-4-one (iso-MeCTI) were found to be 5-6 times more stable than the MeCPI alkylation subunit found in CC-1065 and slightly more stable than even the DSA alkylation subunit found in duocarmycin SA, placing it at the point of optimally balanced stability and reactivity for this class of antitumor agents. Their incorporation into the key analogues of the natural products provided derivatives that surpassed the potency of MeCPI derivatives (3-10-fold), matching or slightly exceeding the potency of the corresponding DSA derivatives, consistent with projections made on the basis of the parabolic relationship. Notable of these, MeCTI-TMI proved to be as potent as or slightly more potent than the natural product duocarmycin SA (DSA-TMI, IC50 = 5 vs 8 pM), and MeCTI-PDE2 proved to be 3-fold more potent than the natural product CC-1065 (MeCPI-PDE2, IC50 = 7 vs 20 pM). Both exhibited efficiencies of DNA alkylation that correlate with this enhanced potency without impacting the intrinsic selectivity characteristic of this class of antitumor agents.

subject areas

  • Alkylation
  • Animals
  • Antiparasitic Agents
  • Cell Line, Tumor
  • Combinatorial Chemistry Techniques
  • DNA
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Administration Schedule
  • Drug Design
  • Indoles
  • Injections, Intraperitoneal
  • Mice
  • Mice, Inbred DBA
  • Molecular Structure
  • Pyrroles
  • Stereoisomerism
  • Survival Rate
  • Xenograft Model Antitumor Assays
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Identity

PubMed Central ID

  • PMC2531197

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja073989z

PubMed ID

  • 17948994
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Additional Document Info

start page

  • 14092

end page

  • 14099

volume

  • 129

issue

  • 45

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