Bleomycins compound

The role of metal speciation in bleomycin uptake and cytotoxicity has been studied extensively. The relatively high amounts of copper in the blood, however,suggest that exogenous or endogenous metals in the blood do not markedly alter the uptake or activity of bleomycin. Nonetheless, a number of other metals can bind to bleomycin including indium and cobalt, and formulating bleomycin with these ex vivo can significantly reduce the cytotoxicity of bleomycin (Lyman et al. 1986). Complexes of this type have been used, however, to examine tumor cell uptake of bleomycin compounds. 

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). 

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. 

All of Hamao U mezawa s work was closely connected with carbohydrates. The principal compounds that he developed, namely, kanamycin, dibekacin (with the elucidation of the resistance mechanism), kasugamycin, formycin, bleomycin, and anthracyclines, are all glycosides. The l.m.w. enzyme-inhibitors, exemplified by bestatin, are mostly oligopeptides, and are the only exceptions. 

Many compounds that damage DNA via radical intermediates have been identified. Some of the agents, such as bleomycin and the enediynes, damage DNA primarily through abstraction of hydrogen atoms. ° In these cases, chemical reactions are directed to certain positions on the DNA backbone by noncovalent binding that places the reactive intermediates in close proximity to particular deoxyribose sugar residues. Similar to the reactions of HO described above, small radicals, such as... 

This was the first report of the successful screening of antibiotics for antitumor activity. Antibiotic research was thus expanded to also cover antitumor research. The term antitumor antibiotics was coined to include those compounds that are produced by microorganisms and inhibit the growth of tumor cells and tumors. Since that time, I have been continuing the study of new antitumor 2Uitlbiotics. Up to now with my collaborators I discovered eibout 65 antitumor antibiotics and elucidated structures of about 50 of them. Among them, bleomycin which we discovered in 1966 (76,79) has been used in the treatment of Hodgkin s lymphoma, tumors of the testis, and carcinomas of the skin, head, neck, and cervix. 

Screening of microbial products has led to the discovery of a number of growth-inhibiting compounds that have proved to be clinically useful in cancer chemotherapy. Many of these antibiotics bind to DNA through intercalation between specific bases and block the synthesis of RNA, DNA, or both cause DNA strand scission and interfere with cell replication. All of the anticancer antibiotics now being used in clinical practice are products of various strains of the soil microbe Streptomyces. These include the anthracyclines, bleomycin, and mitomycin. 

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. 

Among these are intercalating agents such as dauno-mycin (Figs. 5-22, 5-23), neocarzinostatin, and bleomycin (Box 5-B). These are alkylating reagents800 or attack DNA in other ways. The fact that such compounds are in use for chemotherapy emphasizes the need for new approaches to cancer treatment. 

Potent inhibitors of aspartyl proteases have been prepared by incorporating hydroxy-methylene transition-state analogues modified in the a-position. The a-methylene moiety is either functionalized by a heteroatom 16,71 72 or it is dihalogenated)15,73,74 Alkyl substituents in that position are found in several residues present in compounds of natural origin, such as dolaproine (8) in dolastatin 10 and 4-amino-3-hydroxy-2-methylpentanoic acid (9) in bleomycin D (Scheme 1). This position is also substituted in synthetic, conformationally constrained six-membered-ring analogues)75 77 ... 

Coupling of disaccharide unit 30 with tetrapeptide S (21) gives adduct 31 without deliberate protection of the disaccharide or the hydroxy groups of tetrapeptide S and with the sulfo-nium salt in place (Scheme 6). This compound is deprotected and coupled with 7V"-Boc-protected pyrimidoblamic acid (7Va-Boc-12), followed by deprotection, which provides bleomycin A2 (32), identical in all respects to the natural material. 

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. 

Bleomycin Bleomycin is incompatible and loses its potency if it is administered with solutions of benzylpenicillin sodium, carbenicillin, cephazolin or cephalothin sodium, hydrocortisone sodium succinate, mitomycin, methotrexate, nafcillin sodium, aminophylline, ascorbic acid, terbutaline, divalent and trivalent cations (especially copper), compounds containing sulfhydryl groups, and precipitation by hydrophobic anions, essential amino acids, riboflavine, dexamethasone, and frusemide. 

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