Analysis of diazofluorene DNA binding and damaging activity: DNA cleavage by a synthetic monomeric diazofluorene

Angew Chem Int Ed Engl. 2014 Aug 25;53(35):9325-8. doi: 10.1002/anie.201404137. Epub 2014 Jul 9.

Abstract

The lomaiviticins and kinamycins are complex DNA damaging natural products that contain a diazofluorene functional group. Herein, we elucidate the influence of skeleton structure, ring and chain isomerization, D-ring oxidation state, and naphthoquinone substitution on DNA binding and damaging activity. We show that the electrophilicity of the diazofluorene appears to be a significant determinant of DNA damaging activity. These studies identify the monomeric diazofluorene 11 as a potent DNA cleavage agent in tissue culture. The simpler structure of 11 relative to the natural products establishes it as a useful lead for translational studies.

Keywords: DNA cleavage; DNA damage; cancer; natural products.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Binding Sites / drug effects
  • Cattle
  • DNA / chemistry
  • DNA / drug effects*
  • DNA Cleavage / drug effects*
  • DNA Damage*
  • Diazonium Compounds / chemical synthesis
  • Diazonium Compounds / chemistry
  • Diazonium Compounds / pharmacology*
  • Dose-Response Relationship, Drug
  • Fluorenes / chemical synthesis
  • Fluorenes / chemistry
  • Fluorenes / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Diazonium Compounds
  • Fluorenes
  • DNA
  • calf thymus DNA