Bleomycin metal binding sites

Synthetic Study on Man-Made Bleomycins 3.1 Metal-binding Site... 

Time-resolved Raman spectroscopy has been utilized to detect v(Fe-0) in an early intermediate in the reduction of O2 by cytochrome oxidase. " Consideration of other data on dioxygen adducts indicates that this species is most likely the cytochrome al -02 complex. The i/(Fe -02) frequency is elevated relative to that observed for other systems from which it may be concluded that at 10 /jls into the oxidase reaction the 0=0 bond is weakened. The ligand, HAPH (1) (R = H, R = 4-imidazolyl), has been been employed as a model for the metal binding site of Bleomycin [Fe(II)(HAPH)] and [Fe(BLM)] were subjected to oxida-... 

Fig. 7.2. Structure of the copper complex of P-3A, a biosynthetic intermediate of bleomycin showing the probable metal binding sites of bleomycin.

The preceding FID analysis of several metallobleomycins verified that the DNA binding site-selectivities of Co(III) and Fe(III) bleomycin parallel each other quite closely and also correlate to the established cleavage site-selectivity of Fe(II) bleomycin + O2. Notably different, Cu(II) bleomycin did not exhibit an FID assay response under conditions used for the other metallobleomycins. This outcome was likely due to the weaker DNA binding and fast exchange of Cu(II) bleomycin relative to other metallobleomycins (48) and was no doubt exacerbated by the presence of a competitive binding fluorophore. In spite of this limitation, the FID assay is likely to contribute to the study of additional metal complex-DNA interactions in the future. 

Using electrochemistry, uv-visible absorption, esr, and C nmr spectroscopy, and with the help of three new bleomycin analogues, the Fe(II) and Fe(III) binding sites of the antitumor antibiotic bleomycin have been located. The drug appears to utilize the amine-pyrimidine-imidazole region for iron binding. The physical properties of the metal complexes and how those properties relate to the proposed mechanism of action of the anticancer agent is also discussed. 

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