Activated bleomycin, oxidation

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. 

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.

Hecht SM, Long EC, van Atta RB, De Vroom E, Carter BJ (1990) On the mechanism of bleomycin activation and polynucleotide strand scission. In Bleasdale C, Golding BT (eds) Mol. Mech. Bioorg. Processes, Conference Proceedings. Royal. Soc. Chem., London, pp 100-114 Held AM, Halko DJ, Hurst JK (1978) Mechanisms of chlorine oxidation of hydrogen peroxide. J Am Chem Soc 100 5732-5740... 

Oxidative stress reduces the rate of cell proliferation, and that occurring during chemotherapy may interfere with the cytotoxic effects of antineoplastic drugs, which depend on rapid proliferation of cancer cells for optimal activity. Antioxidants detoxify ROS and may enhance the anticancer effects of chemotherapy. For some supplements, activities beyond their antioxidant properties, such as inhibition of topoisomerase II or protein tyrosine kinases, may also contribute. ROS cause or contribute to certain side effects that are common to many anticancer drugs, such as gastrointestinal toxicity and muagenesis. ROS also contribute to side effects that occur only with individual agents, such as doxorubicin-induced cardiotoxicity, cisplatin-induced nephrotoxicity, and bleomycin-induced pulmonary fibrosis. Antioxidants can reduce or prevent many of these side effects, and for some supplements the protective effect results from activities other than their antioxidant properties. Certain side effects, however, such as alopecia and myelosuppression, are not prevented... 

The overall strategy is shown in Figure 2. In the first step, nonradio-active cobalt (II) is bound to bleomycin A2 and air-oxidized to form the stable cobalt (III)-bleomycin A2 complex. The dimethyl(y-aminopropyl)-sulfonium group at the right side of the structure is unique to bleomycin A2 the other bleomycins have quite different terminal amine residues. Since the biological transport properties of all of the bleomycins are similar (17), the structure of the terminal amine residue appears to have relatively little influence on transport into cancer cells therefore this residue is a promising site for chemical modification. 

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). 

The observation of 4 -hydroxylated abasic site 23 allowed to propose the mechanism summarized in Fig. 7 in association to the observation of similar oxidation products previously characterized with Fe-bleomycin or neocarzi-nostatin (4,7). It results in the initial formation of a C4 radical 6 due to H4 abstraction by activated Cu(phen)2. Then a C4 -hydroxylated compound is probably formed. It allows the release of the nucleobase and the formation of 4 -hydroxylated abasic site 23 that is not associated to DNA cleavage. This site was trapped by the authors as a pyridazine after reaction with hydrazine followed by an enzymatic digestion to nucleosides. Oyushi and Sugiyama proposed that a C4 carbocation was involved as intermediate in the reaction, as for Cl -DNA oxidation performed by activated Cu(phen)2. This hypothesis needs, however, to be confirmed since other evolutions of the C4 radical 6, producing also C4 -hydroxylated site, have been proposed with other chemical nucleases (4). However, in the case of DNA oxidation by activated Cu(phen)2 this oxidation pathway seemed minor when compared to the pathway leading to the formation of phosphoglycolate fragment 11. 

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. 

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