Syntheses, structures and reactivities of designed analogues of cobalt(III)- bleomycinsz : Insight into the mechanism of sequence-specific DNA cleavage upon illumination |
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Authors: | Edgardo T. Farinas and Pradip K. Mascharak |
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Affiliation: | (1) Department of Chemistry and Biochemistry, University of California, Santa Cruz, 95064 California, USA |
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Abstract: | Three Co (III) complexes of a designed ligand PMAH that mimics the metal-binding domain of the antitumor antibioticbleomycin (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. |
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Keywords: | Cobalt bleomycin DNA photocleavage spin trap electrophoresis NOE |
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