Bleomycin complexes with metal ions

Bleomycins and their analogues occur naturally as blue copper chelates. Removal of the copper by chemical reduction or complexing agents affords the antibiotics as white solid.s. Copper-free bleomycin is the active. species for chemotherapy, and it has lower toxicity. Bleomycin complexes readily with metal ion.s. which is a key factor in its mode of action. In.sidc the cell, bleomycin forms a chclatc with Fe(ll) that has square pyramidal gcomctiy. Nitrogen atoms from bleomycin occupy five of the po.sitions in this structure. The sixth position may be occupied by the carboxyl group of the carhamate function, but this group is... 

Bleomycin is obtained as an equimolar complex with cupric ion. The copper can be removed by treatment with hydrogen sulfide in methanol solution to give a colorless metal-free BLM, which can be reconverted to the natural copper complex by addition of cupric ion to the aqueous solution, although there are many potential coordination sites in the molecule. Both metal-free and copper-chelated BLMs inhibited growth of microorganisms and mammalian cells, but DNA strand cleavage in vitro was caused only by metal-free BLM, not by the copper-complex. 

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. ... 

Bleomycin is a clinically useful family of glycopeptide antibiotic congeners with antitumoral activity. Cytotoxicity results from oxidative DNA damage. Bleomycin and transition metal ions form complexes that react with dioxygen and oxidize DNA. DNA damage is due to an activated form of iron bleomycin which forms from Fe -bleomycin in the presence of dioxygen and a source of electrons or from Fe -bleomycin in the presence of H2O2. 

RNA hydrolysis, 45 285-287, 297-299 metalloenzymes, 45 251-252 bleomycin, 45 252-260, 299 nucleic acid hydrolysis metal ions and, 45 283-285 by oligonucleotide modified with metal complexes, 45 297-299 of phosphodiesters, 45 251, 287-297 by ribozymes, 45 285-287 cleavage by iron bleomycin, 43 140 polymerase, arsonomethyl phosphonate analogue, 44 201-202 substructures, 43 133-134 transfer... 

The antitumor antibiotic bleomycin (BLM) is believed to cause cytotoxicity through its ability, in the combined presence of dioxygen and a metal ion cofactor (204), to bind to and degrade DNA (205). Iron complexes of BLM have aroused special attention, as such complexes are the first (vide supra concerning the discussion of hemerythrin and hemocyanin) non-heme-iron complexes with a significant capacity for dioxygen activation (206). 

Truter, M. R. Structures of Organic Complexes with Alkali Metal Ions. Vol. 16, pp. 71-111. Umezawa, H., Takita, T. The Bleomycins Antitumor Copper-Binding Antibiotics. Vol. 40,... 

In this section, we briefly introduce the ESR parameters that are obtained for Mn ", Co ", Fe " ", Ni " and Cu " " complexes, using as example one liganding molecule, the antitumor agent, bleomycin, which binds to a multitude of metal ions. The section terminates with an example from the ESR spectra of cupric complexes. Although the discussion of this example is lengthy, the techniques are applicable to other paramagnetic metals. Some limitations of the standard ESR technique are discussed prior to a survey of some of the more sophisticated methods that are available. 

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