Bleomycin active form

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. 

The final species in the above scheme contains the active oxygen (independent of exact electronic description). This analogy is reinforced by the similar chemical reactivity of the activated form of bleomycin and chloroperoxidase [77]. 

In 400 ml of dimethylformamide was dissolved 15.0 g of bleomycinic acid (copper-containing form). To the solution kept at 0°C by cooling were added 1.1 ml of N-methylmorpholine and 10.3 g of 6-chloro-1 -p-chlorobenzenesulfonyloxybenzotriazole (CCBT) as an activating compound. The mixture was stirred for 5 minutes at 0°C, then admixed with 5.3 g of N-[(S)-1 -phenylethyl] -1 3-diaminopropane and further stirred for 1 hour. 

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]. 

Intercalation has been demonstrated with a number of other compounds having a polycyclic aromatic system and groups capable of forming hydrogen bonds. Among such compounds are the antibacterial 9-aminoacridine, the antimalarials mepacrine and chloroquine, the veterinary trypanocide ethidium (246), the thioxanthone lucanthone (247 R = Me) and its more active metabolite hycanthone (247 R = CH20H), which are used in the treatment of schistosomiasis, and the antineoplastic alkaloid ellipticine (248). A number of antibiotics, including the actinomycins, echinomycin and bleomycin, also intercalate. 

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... 

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. 

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... 

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