Antibiotic bleomycin

Clinical study of a new antitumor antibiotic, bleomycin, T. Ichikawa, K. Matsumoto, and H. Umezawa, Int. Congr. Chemother. 5th, Vienna, (1967) 507-516. 

Masjedizadeh and coworkers have recently described similar microwave-promoted hydrogen-deuterium exchange reactions in a series of heterocydes using mixtures of deuterium oxide and deuteriomethanol (Scheme 6.173 b) [328], The rapid exchange method was applied to the deuteration of the anti-tumor antibiotic bleomycin A under catalyst-free conditions [328],... 

Spin-trapping experiments connected with biological superoxide production have also been used to examine the biochemistry of anti-tumour antibiotics bleomycin (Sugiura and Kikuchi, 1978) and mitomycin C (Lown et al., 1978), as well as the effect of iron concentration on xanthine oxidase reactions (Buettner et al., 1978), and the photochemistry of melanins (Felix et al., 1978). 

Various cytotoxic antibiotics bleomycin sulfate mitomycin mitotane... 

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 antibiotic bleomycin, which also binds in the minor groove of B-DNA with some specificity for G-C Sites, forms an iron (II) complex. It can be... 

Galm U, Hager MH, Van Lanen SG, Ju J, Thorson JS, Shen B (2005) Antitumor Antibiotics Bleomycin, Enediynes, and Mitomycin. Chem Rev 105 739... 

Dedon PC, Goldberg IH (1992) Free-radical mechanisms involved in the formation of sequence-de-pendent bistranded DNA lesions by the antitumor antibiotics bleomycin, neocarzinostatin, and calicheamicin. Chem Res Toxicol 5 311 -332... 

Because of its excellent tumor-localizing properties, radiolabelling of the anticancer antibiotic bleomycin has long been of interest. Despite its requirement for iron and... 

Barber et al. (61) have used FAB to study the antibiotics bleomycin A2 and B2 and their metal complexes. In particular, the ferrous sulfate complex of bleomycin A2 shows a pseudomolecular ion at mlz 1566, corresponding to the salt (A2 - H+ + FeS04) since the amide hydrogen of the histidine residue is lost on complexation. An ion at mlz 472 corresponds to the ferrous ion complexed to the surrounding ligands but lacking the disaccharide groups and the peptide chain. 

The antitumour action of the natural antibiotic bleomycin is thought to involve the aerobic degradation of DNA by the Fe2+-bleomycin complex. In order to probe the mechanism of antitumour action of bleomycin, the 4-ethylamido[5,(2 -thienyl)-2-thiophene] imidazole iron(II) complex was synthesized [129]. It was studied in non-aqueous solution using cyclic voltammetry and showed antitumour activity in vitro, its action causing cleavage of the double helical DNA. 

Resistance to the peptide antibiotic/anticancer agent bleomycin can occur through the expression of the Blm family of proteins that sequester the antibiotic. Bleomycin includes... 

The interaction of the anti-tumour antibiotic bleomycin with DNA under conditions of limiting oxygen results in the production of a free nucleic base and an oxidatively damaged sugar-lesion. Studies on d(CGCTGCGT) demonstrate... 

Camptothecin analogs Irinotecan Topotecan Epipodophyllotoxins Etoposide Teniposide Antitumor antibiotics Bleomycin Dactinomycin Daunorubicin Doxorubicin Epirubicin Idarubicin Mitomycin Mitoxantrone Valrubicin Microtubule agents Docetaxel Paclitaxel Vinblastine Vincristine Vinorelbine Enzymes Asparaginase Pegasparaginase Metals... 

Moreover, Sumio Umezawa had broad interests in the chemistry of other sugar-containing antibiotics. Bleomycins are useful antitumor agents discovered by Hamao Umezawa and co-workers in 1966 and are glycopeptides composed of a novel hexapeptide, a terminal amine, and a disaccharide. Collaboration with Hamao s group led to elucidation of the stmctnre of the disaccharide portion common to the bleomycins. For this work Shoji Omoto (Meiji Seika Kaisha) received his Ph.D., and Umezawa, with Tsuchiya and Miyake, synthesized the disaccharide. Later, he and co-workers successfully achieved the first total synthesis of bleomycin A2 in collaboration with the groups of Hamao Umezawa and Masaji Ohno (Professor of the University of Tokyo). 

In their synthesis of the pyrimidine segment of the potent antitumor antibiotic bleomycin, Umezawa, Ohno and coworkers have described the reaction of highly functionalized imine (96) with malonic acid monoethyl ester to afford 3-amino ester (97 equation 16)." The low yield of (97) is largely due to elimination of the amino side chain, giving the corresponding acrylate derivative. A subsequent modification of this reaction using a boron enolate overcomes this problem and will be discussed in Section 4.1.3.2.2.ii. 

The antitumor antibiotic bleomycin has long been of interest in radiopharmacy since it selectively localizes in tumors. In vitro, the drug requires the presence of Fe(II) and oxygen to exhibit its full biochemical activity, which involves introducing both single- and double-strand breaks into cellular DNA through an as yet unidentified radical intermediate Stern and coworkers have recently reported... 

Among the few molecules known to be absorbed selectively by tumor cells is the antitumor antibiotic bleomycin the structure of which is por-... 

Antibiotics Bleomycin Ah++, D++, G+, P++ Pulmonary fibrosis with chronic use. Febrile reaction in 20-25% of patients. 

Antitumor antibiotics bleomycin, enediynes, and mitomycin 05CRV739. Hybrid molecules based on distamycin A as potential antitumor agents 06ARK(7)20. 

Synthetic Studies on Antitumor Antibiotic, Bleomycin. XXIX. For Part XXVIII, see Ref. [61]... 

Using electrochemistry, uv-visible absorption, esr, and C nmr spectroscopy, and with the help of three new bleomycin analogues, the Fe(II) and Fe(III) binding sites of the antitumor antibiotic bleomycin have been located. The drug appears to utilize the amine-pyrimidine-imidazole region for iron binding. The physical properties of the metal complexes and how those properties relate to the proposed mechanism of action of the anticancer agent is also discussed. 

Chemotherapy Reduced generation of free radicals Antibiotics (bleomycin, doxorubin) Erlichman (1992)... 

Direct effects (i.e., effects of hypoxia per se) are mediated via deprivation of molecular Oj and thus reduced generation of free radicals that some chemotherapeutic agents (e.g., the antibiotics bleomycin and doxorubicin Erlichman 1992) and photodynamic therapy require to be maximally cytotoxic. Sparsely ionizing radiation (X- and y-rays) needs Oj for fixation of DNA damage (Fig. 15.1). 

The antitumor antibiotic bleomycin is a mixture of closely related, water-soluble basic glycopeptides, differing only in their terminal amine. For the separation of bleomycins three TLC methods were published (35) ... 

Several synthetic methods have appeared in which derivatives of amino-acids have been reacted with strong base and then with carbon electrophiles. This process has been used in the a-hydroxymethylation of SchifI bases derived from a-amino-acid esters and good yields of /3-hydroxy-a-amino-acids are obtained. This type of compound is also prepared using the optically active imine (183) the t/trco-product was obtained with selectivity ranging from 58 to 92% and optical purity between 43 and 71% (Scheme 88). The jS-hydroxy-a-amino-acid (185) is a constituent of the antibiotic bleomycin and its preparation from L-rhamnose has been described. Studies on the asymmetric synthesis of amino-acids by alkylation of various lactim ethers (186) have continued. L-Alanine, L-valine, and (S)-0,0-dimethyl-a-methyldopa have been used to prepare the heterocyclic intermediates (186), which give a range of amino-acids in high yield and enantiomeric excess. Earlier work has also been extended to the alkylation of the imidazolone anion (187). ... 

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