Iron bleomycin models

Mascharak and co-workers have developed a synthetic analogue system for bleomycin (106, 109-112). In this system, the coordinating functions of BLM (alkyl amines, pyrimidine, peptide nitrogen, and imidazole) are combined in a minimal conf uration for modeling BLM within a ligand termed PMA". In addition to iron, bleomycin also coordinates copper and cobalt, and studies of these forms have been pursued as a source of new information on the physiologically relevant mechanism (17,18 96). The Cu(PMA) complex has been structurally characterized (Fig. 7) (109, 111), and its electronic properties mimic well those of Cu-BLM (113). As with Cu-BLM, a pH-dependent conformational equilihrium exists that interconverts Cu(PMA) with a di-... 

The bleomycins (Fig. 12.6) are a family of glycopeptide-derived antibiotics which are used in the treatment of various tumors. They bind iron in the blood and form an active hypervalent oxo-iron species. The two-dimensional structure is well known but no crystal structures of bleomycin or its metal complexes have been reported. The MM2 force field was modified and extended by modeling of the crystal structures of the cobalt complexes of two bleomycin analogues in order to develop a force field for... 

The presently accepted model for the reaction of bleomycin with DNA involves the binding of an Fe -bleomycin complex to DNA, and the reduction of iron-bound dioxygen. Cleavage of DNA is known to occur by the action of the 1,10-phenanthroline complex of Cu in the presence of hydrogen peroxide, and this reaction is sustained by the presence of NADH. This provides a useful parallel for the bleomycin reaction. 

Section II,A From recent two-dimensional NMR studies on bleomycin analogs, a revisited structural model for specificity, binding, and double-strand cleavage was proposed (367). An investigation of the reaction of Fe "-BLM with iodosylbenzene by ES-MS showed that neither hypervalent iron nor activated oxygen was involved but that hjq)ervalent iodide I(III) was the oxidant (368). 

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