Bleomycin structure

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

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 is composed of five subunits, including a disaccharide, and its structural elucidation relied heavily on 100-MHz H- and 25-MHz C-n.m.r. spectroscopy with the established instruments of that time. 

Jones CB, McIntosh J, Huang H, Graytock A, Hoyt DG (2001) Regulation of bleomycin-induced DNA breakage and chromatin structure in lung endothelial cells by integrins and poly(ADP-ribose) polymerase. Mol Pharmacol 59(l) 69-75... 

Kumar A, Brown DT, Leno GH (2004) DNA intercalators differentially affect chromatin structure and DNA repUcation in Xenopus egg extract. Anticancer Drugs 15(6) 633—639 Kuo MT (1981) Preferential damage of active chromatin by bleomycin. Cancer Res 41(6) 2439—2443 Kuo MT, Sarny TS (1978) Effects of neocarzinostatin on mammalian nuclei release of nucleosomes. Biochim Biophys Acta 518(1) 186—190... 

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. 

In 1972, we elucidated the structure of bleomycin except for the side-chain part of the pyrimidoblamyl moiety (53), and in 1978, we determined the structtire of bleomycin conclxosively, as is shown in Fig. 4 (52). One of the amino acids contained in bleomycin has a pyrimidine ring we named this amino acid "pyrimldo-blamic acid". During the study of biosynthesis, demethylpyrimi-doblamylhistidinylalanine was obtained and its copper complex was crystallized. Based on the x-ray analysis of this crystal (10), we proposed the strvxiturej gf bleomycin in Fig. 4. We also confirmed this structure by N-nmr (25). 

In 1980, in collaboration with Professor Ohno, Faculty of Phanmaceutical Sciences, the University of Tol o, we were successful in the chemical synthesis of pyrimidoblamic acid (84). This was one of the most important parts of the total synthesis of bleomycin. Soon therecifter. Dr. Takita et (55) in my institute were successful in the synthesis of the entire peptide peu t of bleomycin A2 1981 and then in the total synthesis of bleomycin A2 in the same year (56,54). Before this, we chemically converted bleomycin A2 to bleomycin demethyl A2 and estcibllshed synthetic processes for preparing bleonycinic acid from bleomycin demethyl A2 and for preparing various bleomycins from bleonycinic acid (62). Thus, the structures of bleomycins shown in Fig. 4 were conclusively estcibllshed. After our synthesis, Hecht al.also reported on the synthesis of the deglycobleomycin demethyl A2 (3) and the synthesis of bleomycin demethyl A2 (1). 

Fuji et al., the Research Institute of Nihon Kayaku Co. who collaborated with our bleomycin study, isolated 8 peptides from culture filtrates of a bleomycin-producing strain. They were suggested by the structures to be biosynthetic intermediates ofbleo-... 

Although it haus not yet been proven, we have proposed a structure for the bleonycin-iron-02 cstructure different from ours for the bleomycin-Fe2 -00 complex. On the basis of pmr amalysis, the same authors (32, 31) later reported that the steric relationship between the a-methin proton of the a-aminocarboxamide part of the pyrimidoblamyl moiety and the adjacent methylene protons is different from that in the deme-thylpyrimidoblainylhistidylalauiine-Cu coniplex crystals (shown by x-ray analysis) (10) and deglycobleomycin-Fe2+-C0 conplex. 

The anthracycline antibiotics, which include doxorubicin, daunorubicin, bleomycin, and mitomycin C, inhibit DNA and RNA synthesis. Doxorubicin also interfers with topoisomerase II (a DNA gyrase), the activity of which is markedly increased in proliferating cells. Structurally related to doxorubicin are epirubicin and mitozantrone. The cytotoxic antibiotics are used to treat leukaemias and lymphomas and also for solid tumours in the breast, lung, thyroid and ovary. Cardiotoxicity is the major dose-limiting factor, with arrhythmias and myocardial depression (Bacon and Nuzzo 1993). The chronic phase of cardiotoxicity is a dose-dependent cardiomyopathy that leads to congestive heart failure in 2-10% of patients. Myocardial injury is the result of oxygen free radical formation. Children are particularly sensitive to these cardiotoxic reactions and may require a heart transplant in their later years. Epirubicin is less cardiotoxic than doxorubicin. 

Structural studies on bleomycin and its transition metal complexes 728... 

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