Complexes of Bleomycin

The metal binding ability of bleomycin was apparent from its isolation as the copper chelate, and derivatives of interest besides Cu and Fe (see 

Section 7.4), include Co(n) and Co(III) [18-22], Mn(II) [23, 24], Zn(II) [25, 26], Ni(H) [27], Ru(III) [28], Tc [29], and V(IV) [30]. Earlier results have been summarized [3]. Many of these examples may be considered to be attempts at producing tumour-localizing agents, combining the known affinity of bleomycin for tumour cells with a suitably stable metal radiolabel. The metallation does appear to affect tissue distribution, which may imply an alteration in functional structure of the drug. A study of the cytotoxic and antitumour properties of some metal complexes gave an order of activity in culture and antitumour potency of Cu(II)BLM BLM Zn(II)BLM Fe(III)BLM Co(II)BLM [31]. 

The formation of Cu(II)—BLM species is pH dependent with at least two complexes identified [32, 33]. A reduction potential of —319 mV (vs. NHE) has been assigned to the Cu(II)/Cu ) couple [34]. The Cu(II) complex is kinetically and thermodynamically stable to ligand substitution, being only slowly reduced by sulfhydryls [35]. Metal exchange is fast for Cu(I) and the binding sites may not be identical to those for Cu(II), as indicated by potentiometric and NMR data [34]. Further, reduction in the presence of the Cu(I[) species of Fe(II) results in metal displacement [36], 

The Co(II) adduct has ESR features indicative of a low-spin configuration with the unpaired electron in the 2 ground state [18, 19]. In the presence of oxygen, the ESR features are characteristic of a monooxygenated low-spin Co(II)—O2 adduct [19]. In the presence of DNA, the ESR parameters again change, and this was attributed to a different orientation of the bound O2 molecule. The presence of more than one complex. 

The dimerization has a second-order rate constant of 200 50 M s at 25 C, which is lowered by a factor of 2 X 10 in the presence of DNA [21]. An apparent equilibrium binding constant of 8.4 X 10 was found for the Co(III)—O2—Co(III)/DNA adduct, with binding of one //-peroxo complex approximately every three base pairs [21]. Of interest is the fact that the variously colored Co complexes have the ability to nick DNA in the presence of light [42, 43], reminiscent of the reaction of simple Co(III) complexes (Section 1.3.1). As the Co-substituted bleomycin has been extensively investigated for tumour imaging and found to accumulate selectively in certain cancer cells, the possibility of selective attack by a later light-induced reaction is attractive. 

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Nucleic acid recognition by metal complexes of bleomycin 99CRV2797. 

Barber et al. (61) have used FAB to study the antibiotics bleomycin A2 and B2 and their metal complexes. In particular, the ferrous sulfate complex of bleomycin A2 shows a pseudomolecular ion at mlz 1566, corresponding to the salt (A2 - H+ + FeS04) since the amide hydrogen of the histidine residue is lost on complexation. An ion at mlz 472 corresponds to the ferrous ion complexed to the surrounding ligands but lacking the disaccharide groups and the peptide chain. 

Fig. 7. Electronic absorption spectra of Cu-complexes of bleomycin and phleomydn...

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 biochemical basis for bleomycin cytotoxicity and pulmonary toxicity may involve the generation of reactive oxygen species by a complex of bleomycin with iron. This complex has been shown to catalyse the formation of 02 and HO capable of causing DNA strand excision (Sausville et al. 1978) and lipid peroxidation (Kameda et al. 1979). 

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