Iron bleomycin structure

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-... 

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... 

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. 

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... 

Neese F, Zaleski JM, Zaleski KL, Solomon El (2000) Electronic structure of activated bleomycin oxygen intermediates in heme versus non-heme iron. J Am Chem Soc 122 11703-11724... 

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... 

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

EPR spectroscopy has been a powerful tool to investigate radiolytic events in nonheme complexes . Very recently, the signature EPR spectrum for the Fe -OOH intermediate in activated bleomycin was calculated , and the analysis of electronic structure of this complex provides a detailed insight into the chemical stability of Fe -OOH moiety. Neese also noted that the side-on coordinated iron-peroxide is not activated for 0-0 bond cleavage . ... 

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.

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). 

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. 

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