Iron-bleomycin activated

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]. 

Burger RM, Kent TA, Horwitz SB, Munck E, Peisach J (1983) Mossbauer study of iron bleomycin and its activation intermediates. J Biol Chem 258 1559-1564 Burger RM, Freedman JH, Horwitz SB, Peisach J (1984) DNA degradation by manganese(l)-bleomy-cin plus peroxide. Inorg Chem 23 2215-2217... 

The natural product bleomycin mediates strand scission in the presence of iron and oxygen by a related mechanism (6, 12, 14) however, no diffusible intermediate is generated. Electrochemical and related studies showed that the mechanism of iron bleomycin (Fe-BLM) involves first reduction of Fe(III)-BLM, reaction of Fe(II)-BLM with 02, and reduction of the Fe(II)-BLM-02 adduct to activated Fe-BLM (15). 

J. W. Sam, X. J. Tang, J. Peisach, Electrospray mass spectrometry of iron bleomycin Demonstration that activated Bleomycin is a ferric peroxide complex, J. Am. Chem. Soc. 116 (1994) 5250. 

Iron bleomycin (FeBLM) is a natural product with anticancer activity that is thought to arise from nucleic acid damage and has been termed... 

Fig. 4. Mechanism of the oxidative DNA cleavage by activated iron-bleomycin.

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). 

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. 

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... 

Bleomycin 4.28), the most clinically used of all metal-binding anti-cancer drugs, uses its bound iron to activate atmospheric oxygen and, finally, degrade DNA (Section 4.0.4). 

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. 

Gutteridge, J.M.C. (1987). Bleomycin-detectable iron in knee-joint synovial fluid from arthritic patients and its relationship to the extracellular activities of caeruloplasmin, transferrin and lactoferrin. Biochem. J. 245, 415-421. 

Metal-mediated antibiotics like bleomycin, which requires iron or other metals for activity... 

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). 

The reaction pathway appears to involve the formation of superoxoiron(III) bleomycin prior to that of activated bleomycin , which appears to be a peroxoiron(III) complex, although the source of the second electron is uncertain. Activated bleomycin can be synthesized directly by reaction of hydrogen peroxide with iron(III)-bleomycin. In the absence of DNA, activated bleomycin decays to the Fem complex, with damage to the antibiotic. In the presence of DNA, degradation products appear with a rate of formation equal to the rate of loss of activated bleomycin. The polymeric products of DNA degradation have not been characterized, but they decompose to give free bases, released in the sequence T> C> A> G. 

Since H202 is easier to handle than 02, we will focus on the use of the former. Many metals can be used for this transformation [50]. Among them, iron compounds are of interest as mimics of naturally occurring non-heme catalysts such as methane monooxygenase (MMO) [51a] or the non-heme anti-tumor drug bleomycin [51b]. Epoxidation catalysts should meet several requirements in order to be suitable for this transformation [50]. Most importantly they must activate the oxidant without formation of radicals as this would lead to Fenton-type chemistry and catalyst decomposition. Instead, heterolytic cleavage of the 0—0 bond is desired. In some cases, alkene oxidation furnishes not only epoxides but also diols. The latter transformation will be the topic of the following section. 

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... 

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