The biological activity of the antitumor antibiotic, bleomycin-A2, is believed to be due, at least in part, to its interactions with and degradation of DNA which is mediated by metal ions and oxygen. NMR spectroscopy will be used to study the structure and dynamics of (i) bleomycin-A2 in free solution, (ii) bleomycin-A2 complexes with various synthetic DNA's, (iii) diamagnetic and paramagnetic complexes of bleomycin-A2 with various transition metal ions and lanthanides, (iv) ternary complexes of bleomycin-A2, DNA and metal ions, and (v) quaternary complexes of bleomycin-A2, DNA, metal ions and oxygen analogs. These data, together with data obtained from studies on the degradation of DNA, will be used to formulate a mechanism for the degradation mechanism. An understanding of this mechanism will facilitate the optimization of clinical use of bleomycin and provide a basis for the rational design of bleomycin derivatives with improved therapeutic activity.
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