Bleomycin iron complexes

Bleomycin, an antitumour antibiotic, binds iron in the reduced, divalent state to its secondary amide group. It binds low molecular weight iron ions (often loosely referred to as free iron) in forms that catalyse free radical reactions (Gutteridge et al., 1981) but not iron bound within native, functional protein structures, such as ferritin, transferrin, lactoferrin, haemoglobin, myoglobin, cytochromes etc. The resulting bleomycin-iron complex is capable of degrading DNA... 

Interference with the formation of the bleomycin-iron complex may be the most effective way of controlling bleomycin pulmonary toxicity, a fibrosis... 

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). 

Structure of bleomycin and its proposed iron complex (reproduced by permission from Reference 25). 

Fig. 2. Different routes for the generation of activated bleomycin. The formal oxidation state (V) of the bleomycin-iron-oxo species (perferryl complex) is two oxidant equivalents above BLM-Fe ", but one oxidant equivalent might be located on the ligand, as in Compound I of peroxidases, with an iron" -oxo-ligand radical cation structure.

There are now more than forty drugs approved for the treatment of human cancer in the United States. Considering the thousands of compounds that have been tested as candidate antitumor agents, this is a highly select group. Among them are two drugs that require a metal ion as part of their structures. One is the simple metal complex cis-diamminedichloroplatinum(ii). The other, bleomycin, is a natural product that must form an iron complex to display cytotoxicity. In addition, two anthracycline natural products, doxorubicin or adriamycin, and daunomycin, may also function as iron complexes or utilize cellular iron in an indirect way in their mechanisms of action. 

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. ... 

Further evidence that the pyrimidine is bound in the iron derivatives can be seen in the difference spectra shown in Figure 5. Both of the complexes exhibited a pyrimidine ir-ir electronic transition which was shifted from its original position in bleomycin. This band occurs at 230 nm in the free drugs and shifts to 250 nm in their metalloderivatives. In addition, the iron complexes exhibit a second strong envelope at 300 nm. Since transitions due to two chromophores present in the antibiotics, the n of the pyrimidine and the ir-ir of the bithiazole moiety, overlap at 290 nm, the origin of the band at -300 nm in the difference spectra of the metalloderivatives is difficult to determine. 

From a biological perspective the bleomycin (BLM) family of antibiotics that are used widely in chemotherapy, have stimulated considerable effort in understanding oxygen activated iron complexes. In particular iron bleomycin reacts with oxygen to form the so-called purple species, which exhibits an absorption band around 600 nm that is now known to be characteristic of the Fe -OOH species. In the case of Fe-BLM the active intermediate has been identified spectroscopically as a low-spin Fe -hydroperoxide. Several structural mimics of the metastable purple Fe -OOH species have been prepared, in particular complexes with neutral pentadentate ligands e.g., l,l-di(pyiidin-2-yl)-N,N-bis(pyridin-2-ylmethyl)-ethanamine (N4Py) Resonance Raman spectroscopy has proven... 

Guajardo and Mascharak have found that the iron complexes [Fe(PMA)] (n = 1, 2) (84, 85) shown in Fig. 23, which are synthesized as iron bleomycin analogues, promote facile lipid peroxidation in the presence of O2 or H2O2 [140]. Reaction of linoleic acid (59) with O2 catalyzed by 84 and 85 gives the 13-OOH product in the selectivity of 80 and 75%, respectively. In the reaction of arachidonic acid, (86), the 15-OOH product is also selectively formed (80%) by the two complexes. The peroxidation is also promoted by H2O2. As a possible intermediate, a low-spin (hydroperoxo)-iron(III) species, [(PMA)Fe -OOH], has been detected by X-band EPR. The EPR spectrum is identical to that of the activated bleomycin. The reaction has been explained in terms of the radical mechanism, which involves H atom abstraction from lipid (LH) by [(PMA)Fe -OOH]. Peroxidized linoleic acid (L-00 ) has been detected by UV absorption at 234 nm, and a chain propagation reaction by the peroxy radical to produce lipid hydroperoxide (L-OOH) has been proposed. 

To mimic the square-pyramidal coordination of iron bleomycin, a series of iron (Il)complexes with pyridine-containing macrocycles 4 was synthesized and used for the epoxidation of alkenes with H2O2 (Scheme 4) [35]. These macrocycles bear an aminopropyl pendant arm and in presence of poorly coordinating acids like triflic acid a reversible dissociation of the arm is possible and the catalytic active species is formed. These complexes perform well in alkene epoxidations (66-89% yield with 90-98% selectivity in 5 min at room temperature). Furthermore, recyclable terpyridines 5 lead to highly active Fe -complexes, which show good to excellent results (up to 96% yield) for the epoxidation with oxone at room temperature (Scheme 4) [36]. 

The bleomycins (50) are hardly simple amines, but they do have two NH2 groups and a CONH2 group at the N-terminal domain, as well as potential donor nitrogens in pyrimidine and imidazole, which can complex metal ions." " The complexing of iron to bleomycin" " " has a significant effect on bleomycin-DNA interactions—metal complexes can mediate strand scission—and on alkene oxidation. Both may involve hydroperoxide intermediates." " " " ... 

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... 

Although it haus not yet been proven, we have proposed a structure for the bleonycin-iron-02 cstructure different from ours for the bleomycin-Fe2 -00 complex. On the basis of pmr amalysis, the same authors (32, 31) later reported that the steric relationship between the a-methin proton of the a-aminocarboxamide part of the pyrimidoblamyl moiety and the adjacent methylene protons is different from that in the deme-thylpyrimidoblainylhistidylalauiine-Cu coniplex crystals (shown by x-ray analysis) (10) and deglycobleomycin-Fe2+-C0 conplex. 

Bleomycin is a naturally occurring fermentation product of Streptomyces verticillus. It is a basic glycoprotein, complexed with Cu++. It intercalates between DNA base pairs, and it also chelates iron, generating oxygen radicals which further damage the DNA. It is the only cell-cycle specific agent among the antibiotics as it causes accumulation of cells in the G2 phase of the cell cycle. 

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