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

摘要

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 havebeen 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 micromo-lar 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.