Bleomycin,

Bleomycin (Blenoxane) causes chain scission and fragmentation of DNA. With the exception of the skin and lungs, most tissues can enzymatically inactivate bleomycin. Bleomycin is used in the management of squamous cell carcinoma of the head, neck, and esophagus in combination with other drugs in patients with testicular carcinoma, and in the treatment of Hodgkin s disease and other lymphomas. Bleomycin causes stomatitis, ulceration, hyperpigmentation, erythema, and pulmonary fibrosis. 

The bithiazole group of the bleomycins, BLMs (Fig. 12.12), intercalates into the minor groove of DNA (Povirk et al. 1979). The transition metal ions are co-ordinated by various nitrogens as indicated by asterisks (for a review of the coordination of BLMs, see Dabrowiak 1980 for more recent data, see Chikira et al. 2000 Kemsley et al. 2003). 

A mechanism that accounts for the major aspects of the BLM chemistry is shown below (for some potential variations see Rashid et al. 1999). Upon reacting activated BLM, Fe(III)BLMOOH, with DNA a C(4 ) radical and a Fe(IV)BLM=0 species are formed [reaction (50)]. The latter is still attached to DNA. In the absence of 02 and/or in competition to an 02-addition to the C(4 ) radical [reaction (53)], the Fe(IV)BLM=0 species may add to the C(4 ) radical [reaction (51)]. One also may consider an outer-sphere one-electron oxidation by the Fe(IV) species which would be equivalent as the resulting products are concerned. The final 

The formation of base propenals is not as straight-forward. From the above, it is clear that 02 is required for the formation of the base propenals. After the formation of the C(4 ) peroxyl radical [reaction (53)], the Fe(IV)BLM species has to interact with this peroxyl radical, possibly by forming an adduct [reaction 

The above scheme does not fully reflect the present view expressed in the literature, but retains essential elements. In the literature one usually finds as one of the intermediates the 4 -hydoperoxide. This is a species that should also be formed when the C(4 )-peroxyl radical reacts with 02, conditions that prevail in the y-radiolysis of DNA in oxygenated aqueous solution, but under these conditions, no trace of base propenals is formed (Sect. 12.4.4). In early mechanistic proposals, the geminal phosphatohydrine has been assumed to be an intermediate with the substantial lifetime of tens of minutes. 

the corresponding geminal chlorohydrines have a lifetime of less than a few ps (Mertens et al. 1994). The related (i-Pr0)2P(0)0C(CH3)20H decays with k 3 x 104 s 1, and the data on the peroxyl radical chemistry of trimethylphosphate (Schuchmann, von Sonntag 1984) will have to be reinterpreted in so far as the decay of (CH30)2P(0)CH20H into dimethylphosphate and formaldehyde must have occurred during the bimolecular decay of the peroxyl radicals, i.e. on the submillisecond time scale. 

Colorless or yellowish powder that becomes bluish depending on Cu content.1 

Very soluble in water and methanol slightly soluble in ethanol practically insoluble in acetone, ethyl acetate, butyl acetate, and ether.1 

Bleomycins are thought to react with DNA and cause strand scission they have also been shown to have a type of oxygen transferase activity.1 

Fever (4-6 hours) and chills, anorexia, and vomiting. Patients over age 50 may have pulmonary complications.2 

Wear rubber gloves, protective clothing, and goggles. Work in the fume hood. To 10 mL of an aqueous solution containing 10 mg of bleomycin (in a 100-mL, round-bottom flask) add 10 mL of 50% hydrochloric acid (5 mL of concentrated hydrochloric acid slowly added to 5 mL of cold water). Gently boil the mixture (preferably under reflux) for 4 hours. After cooling, neutralize the solution by slowly adding soda ash or 10% sodium hydroxide solution. Wash liquid into the drain water.3 

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Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Bleomycin and cyclosporine are the two economically most important streptomycete peptide antibiotics used as antitumor agents and immunomodulators, although dactinomycin is important medically for several tumors (see Chemotherapeutics, anticancer Immunotherapeutic agents). 

Fig. 13. Structure of the bleomycin-Fe(II)-02 complex showing the DNA binding region.

Bleomycin sulfate is used alone or in combination with other antineoplastic dmgs. Using this DNA-cleaving dmg, disease-free (possibly cured) survivors of some cancers have been seen, especially with the use of bleomycin in multidmg regimens. General reviews of bleomycin (234,242—245) and its mechanism of action (246—249) are available. 

The stmcture of bleomycin shown in Figure 13 was reported in 1978 (250) total synthesis was reported in 1982 (251—253). The commercial fermentation and purification of bleomycin has been described (244) as has its nonribosomal synthesis using a large multien2yme complex (254). 

Bleomycin sulfate USP, a white or yellowish powder, is very soluble in water and sparingly soluble in alcohol. It is 55—70% bleomycin A2 and 25—32% bleomycin based on total bleomycin base content as deterruined by hplc. This combination was found to be more effective than use of either bleomycin alone (234). 

Newer bleomycins such as peplomycin and especially liblomycin, are more resistant to bleomycin hydrolase. This results in less lung toxicity but more bone marrow toxicity, and allows for a different spectmm of antitumor action. Bleomycin is inactive orally it is given intravenously, intramuscularly, subcutaneously, or directiy into a cavity such as the pleural cavity. The majority of dmg is excreted unchanged in the urine. 

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

Oligosaccharides also occur widely as components (via glycosidic bonds) of antibiotics derived from various sources. Figure 7.20 shows the structures of a few representative carbohydrate-containing antibiotics. Some of these antibiotics also show antitumor activity. One of the most important of this type is bleomycin A2, which is used clinically against certain tumors. 

Bleomycin A2 (an antitumor agent u.sed clinically again.st. specific tumors)... 

The irradiation a 1 1 Cu-peplomycin complex, an antibiotic of the bleomycin family (Fig. 15), leads to a product of an isomerization of a thiazole ring. In this case, the compound converted from a 2,4 -bithiazole to a 4,4 -bithiazole derivative. When a 5 1 Cu - peplomycin complex was used, the product was a 3-isothiazolyl-4-thiazole derivative (86JA7089 87JA938). 

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