Cobalt -bleomycin complex

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 overall strategy is shown in Figure 2. In the first step, nonradio-active cobalt (II) is bound to bleomycin A2 and air-oxidized to form the stable cobalt (III)-bleomycin A2 complex. The dimethyl(y-aminopropyl)-sulfonium group at the right side of the structure is unique to bleomycin A2 the other bleomycins have quite different terminal amine residues. Since the biological transport properties of all of the bleomycins are similar (17), the structure of the terminal amine residue appears to have relatively little influence on transport into cancer cells therefore this residue is a promising site for chemical modification. 

The interaction of bleomycin with metal ions and the chemistry associated with this interaction has been the focus of numerous studies aimed at elucidating the detailed mechanism of action of this drug. A recent paper notes that the interaction of bleomycin with iron gives a reactive intermediate which cleaves DNA. Ferrous ion-bleomycin interaction results in chemiluminescence suggesting that the activated intermediate may be electronically excited, Mossbauer studies of the ferrous and ferric bleomycin complexes indicated that the latter complex may exist in two distinct conformations. In a study of cobalt-bleomycin complexes, the existence of a cobalt-bleomycin-hydroperoxide complex capable of nicking DNA has been demonstrated. ... 

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-... 

While the degradation of DNA in vitro by bleomycin - Fe2+ has been firmly associated with the generation of base propenal species, it is now reported that a small amount of 8-hydroxyguanine is also formed in the DNA, in a dose-dependent manner. O Curiously, using bleomycin - Fe2+ with Ehrlich ascites cells in culture, no base propenal or 8-hydroxyguanine formation could be demonstrated, even in conditions of quantitative cell kill. The green complex of bleomycin A2 and cobalt... 

The role of metal speciation in bleomycin uptake and cytotoxicity has been studied extensively. The relatively high amounts of copper in the blood, however,suggest that exogenous or endogenous metals in the blood do not markedly alter the uptake or activity of bleomycin. Nonetheless, a number of other metals can bind to bleomycin including indium and cobalt, and formulating bleomycin with these ex vivo can significantly reduce the cytotoxicity of bleomycin (Lyman et al. 1986). Complexes of this type have been used, however, to examine tumor cell uptake of bleomycin compounds. 

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