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Total synthesis and evaluation of iso-duocarmycin SA and iso-yatakemycin

Academic Article
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Overview

related to degree

  • Macmillan, Karen Smith, Ph.D. in Chemistry, Scripps Research 2004 - 2009

authors

  • Macmillan, Karen Smith
  • Nguyen, T.
  • Hwang, I.
  • Boger, Dale

publication date

  • January 2009

journal

  • Journal of the American Chemical Society  Journal

abstract

  • The total synthesis and evaluation of iso-duocarmycin SA (5) and iso-yatakemycin (6), representing key analogues of the corresponding natural products incorporating an isomeric alkylation subunit, are detailed. This pyrrole isomer of the natural alkylation subunit displayed an enhanced reaction regioselectivity and a 2-fold diminished stability. Although still exceptionally potent, the iso-duocarmycin SA derivatives and natural product analogues exhibited a corresponding approximate 3-5-fold reduction in cytotoxic activity [L1210 IC(50) for (+)-iso-duocarmycin SA = 50 pM and for (+)-iso-yatakemycin = 15 pM] consistent with their placement on a parabolic relationship correlating activity with reactivity. The DNA alkylation selectivity of the resulting key natural product analogues was unaltered by the structure modification in spite of the minor-groove presentation of a potential H-bond donor. Additionally, a unique ortho-spirocyclization with such derivatives was explored via the preparation, characterization, and evaluation of 34 that is incapable of the more conventional para-spirocyclization. Although 34 proved sufficiently stable for isolation and characterization, it displayed little stability in protic solvents (t(1/2) = 0.19 h at pH 3, t(1/2) = 0.20 h at pH 7), a pH-independent (H(+) independent) solvolysis rate profile at pH 3/4-7, and a much reduced cytotoxic potency, but a DNA alkylation selectivity and efficiency comparable to those of duocarmycin SA and iso-duocarmycin SA. The implications of these observations on the source of the DNA alkylation selectivity and catalysis for this class of natural products are discussed.

subject areas

  • Alkylation
  • Animals
  • Biological Products
  • Cell Line, Tumor
  • Cell Survival
  • DNA
  • Indoles
  • Isomerism
  • Mice
  • Molecular Structure
  • Pyrroles
  • Solubility
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2646182

International Standard Serial Number (ISSN)

  • 0002-7863

Digital Object Identifier (DOI)

  • 10.1021/ja808108q

PubMed ID

  • 19154178
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Additional Document Info

start page

  • 1187

end page

  • 1194

volume

  • 131

issue

  • 3

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