Bleomycin intercalation

Bleomycin intercalates between bases (f d ouble-stranded DNS(34). In this connection, it is interesting that phleomycin which has the dihydrobithiazole moiety, does not intercalate with DNA (33). It causes more single-strand scission than double-strand scission (30). 

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... 

Bleomycin is a naturally occurring fermentation product of Streptomyces verticillus. It is a basic glycoprotein, complexed with Cu++. It intercalates between DNA base pairs, and it also chelates iron, generating oxygen radicals which further damage the DNA. It is the only cell-cycle specific agent among the antibiotics as it causes accumulation of cells in the G2 phase of the cell cycle. 

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. 

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). 

Povirk LF, Flogan M, Dattagupta N (1979) Binding of bleomycin to DNA intercalation of the bithia-zole rings. Biochemistry 18 96-101... 

Figure 6, Schematic of 1 in the presence Co(III) bleomycin B2 green and the nucleotide numbering referred to in the text BT, intercalated bithiazole dashed line, oligonucleotide dyad axis (top). H-G crystal structure ofDNA-bound Co(III) bleomycin B2 green (bottom).

Bleomycin G2/M-phase-specific Bithiazole rings intercalate into DNA strand. Drug oxidizes Fe " ", yielding free radicals which damage DNA. ... 

The commercially available bleomycin drug product is a mixture of naturally occurring glycopeptides, predominantly bleomycin A2 (Fig. 42.17). The aromatic bithiazole ring system can intercalate DNA, but unlike most of the antibiotics discussed thus far, the molecule does not inhibit topoisomerase II. Rather, intercalation positions bleomycin for DNA destruction via cytotoxic free radicals. The disaccharide,... 

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