Syntheses, structures and reactivities of designed analogues of cobalt(III)-bleomycinsz: Insight into the mechanism of sequence-specific DNA cleavage upon illumination

Edgardo T. Farinas, Pradip K. Mascharak

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Three Co (III) complexes of a designed ligand PMAH that mimics the metal-binding domain of the antitumor antibiotic bleomycin (BLM) have been isolated and structurally characterized. The coordination structures of the various forms of Co(III)-BLMs have been established on the basis of spectral similarities between these synthetic analogues and the corresponding Co(III)-BLMs. All three analogues, like Co(III)-BLMs, induce DNA strand scission upon UV illumination. Both DNA cleavage and spin trapping experiments demonstrate that UV irradiation of the analogues generates a C/N-based radical on the ligand framework which rapidly reacts with water to produce -OH radical near the DNA helix and causes strand scission. A similar mechanism could account for the photoactivity of the Co(III)-BLMs. Covalent attachment of DNA-binding groups to these analogues enhances the DNA-affinities and photocleavage efficiencies to a great extent. The hybrid analogues promote sequence-specific DNA photodamage at micromolar concentrations. The metallated cores of the hybrid analogues are the primary determinant of the observed sequence-specificity. Details of the mode of binding of the hybrid analogues to DNA have been explored by NMR techniques.

Original languageEnglish (US)
Pages (from-to)459-476
Number of pages18
JournalProceedings of the Indian Academy of Sciences - Chemical Sciences
Volume107
Issue number4
DOIs
StatePublished - Aug 1 1995
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Chemistry(all)

Keywords

  • Cobalt
  • DNA
  • NOE
  • bleomycin
  • electrophoresis
  • photocleavage
  • spin trap

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