Bleomycin interaction

The interaction of bleomycin with metal ions and the chemistry associated with this interaction has been the focus of numerous studies aimed at elucidating the detailed mechanism of action of this drug. A recent paper notes that the interaction of bleomycin with iron gives a reactive intermediate which cleaves DNA. Ferrous ion-bleomycin interaction results in chemiluminescence suggesting that the activated intermediate may be electronically excited, Mossbauer studies of the ferrous and ferric bleomycin complexes indicated that the latter complex may exist in two distinct conformations. In a study of cobalt-bleomycin complexes, the existence of a cobalt-bleomycin-hydroperoxide complex capable of nicking DNA has been demonstrated. ... 

Bleomycins are glycopeptide antibiotics, isolated from Streptomyces verticillus. Bleomycins interact with DNA and induce breakage of DNA with a concomitant release of free bases. Bleomycin A (312) inhibits the replication of W [18]. 

Bis(aminoalkyl)bithiazoles are useful as DNA cleavage agents. Bleomycin contains a 2,4 -bithiazole moiety which plays an important role in the interaction with double stranded DNA during the cleavage reaction. The 2,2 -bis(aminomethyl)-4,4 -bithiazole (70) has been synthesised by the condensation of l,4-dibromobutane-2,3-dione with Boc-glycinethioamide... 

Although, as stated above, we wiU mostly focus on hydrolytic systems it is worth discussing oxidation catalysts briefly [8]. Probably the best known of these systems is exemphfied by the antitumor antibiotics belonging to the family of bleomycins (Fig. 6.1) [9]. These molecules may be included in the hst of peptide-based catalysts because of the presence of a small peptide which is involved both in the coordination to the metal ion (essential co-factor for the catalyst) and as a tether for a bisthiazole moiety that ensures interaction with DNA. It has recently been reported that bleomycins will also cleave RNA [10]. With these antibiotics DNA cleavage is known to be selective, preferentially occurring at 5 -GpC-3 and 5 -GpT-3 sequences, and results from metal-dependent oxidation [11]. Thus it is not a cleavage that occurs at the level of a P-O bond as expected for a non-hydrolytic mechanism. 

Portugal J, Waring MJ (1987) Interaction of nucleosome core particles with distamycin and echinomycin analysis of the effect of DNA sequences. Nucleic Acids Res 15(3) 885-903 Povirk LF, Goldberg IH (1987) A role of oxidative DNA sugar damage in mutagenesis by neocarzino-statin and bleomycin. Biochimie 69(8) 815-823... 

Steighner RJ, Povirk LF (1990) Bleomycin-induced DNA lesions at mutational hot spots imphcations for the mechanism of double-strand cleavage. Proc Natl Acad Sci USA 87(21) 8350-8354 Straney DC, Crothers DM (1987) Effect of drug-DNA interactions upon transcription initiation at the lac promoter. Biochemistry 26(7) 1987-1995... 

Takeshita M, Grollman AP, Ohtsubo E, Ohtsubo H (1978) Interaction of bleomycin with DNA. Proc... 

The bleomycins (50) are hardly simple amines, but they do have two NH2 groups and a CONH2 group at the N-terminal domain, as well as potential donor nitrogens in pyrimidine and imidazole, which can complex metal ions." " The complexing of iron to bleomycin" " " has a significant effect on bleomycin-DNA interactions—metal complexes can mediate strand scission—and on alkene oxidation. Both may involve hydroperoxide intermediates." " " " ... 

Goldiner PL, Shams A. Bleomycin-oxygen interaction. Semin Anesth 1993 12 79-82. 

Kemsley JN, Zaleski KL, Chow MS, Decker A, Shishova EY, Wasinger EC, Hedman B, Hodgson KO, Solomon El (2003) Spectroscopic studies of the interaction of ferrous bleomycin with DNA. J Am Chem Soc 125 10810-10821... 

Natrajan A, Hecht SM (1994) Bleomycins mechanism of polynucleotide recognition and oxydative degradation. In Neidle S, Waring M (eds) Molecular aspects of anticancer drug-DNA interactions. MacMillan, London, pp 197-242... 

Similarly, resistance to the anticancer antibiotic mitomycin in the producing organism, Streptomyces lavendulae, occurs via sequestration of the antibiotic by the binding protein MRD (81, 82). This protein interacts with the mitomycin export system, thus additionally facilitating export of the antibiotic from the cell. The structure of MRD reveals similarity to the bleomycin resistance proteins and, in fact, the protein can also bind bleomycin and confer resistance to this antibiotic (83). 

Microbial sources have been a very rich source for cancer chemotherapeutic agents. Of particular note is the Strep-tomyces spp., which has been responsible for the production of many approved anticancer agents that are in clinical practice. These agents are represented by highly diverse structural classes exemplified by the anthracycline family (e.g., doxom-bicin, 73) (72-74), actinomycin family (e.g., dactinomycin, 74), glycopeptides family (e.g., bleomycins A2 and B2, 75 and 76) (75), and mitomycin family (e.g., mitomycin C, 77) (72, 76). All these compounds specifically interact with DNA for then-mode of action. 

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... 

Bleomycin Phenytoin Reduced effect of phenytoin interaction poorly documented Unknown... 

Clinically important, potentially hazardous interactions with altretamine, amikacin, aminoglycosides, antineoplastics, bleomycin, busulfan, carboplatin, carmustine, chlorambucil, cisplatin, corticosteroids, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, docetaxel, doxorubicin, estramustine, etoposide, fludarabine, fluorouracil, gemcitabine, gentamicin, hydroxyurea, idarubicin, ifosfamide, indomethacin, kanamycin, levamisole, lomustine, mechlorethamine, melphalan, mercaptopurine, methotrexate, mitomycin, mitotane, mitoxantrone, neomycin, pentostatin, plicamycin, procarbazine, streptomycin, streptozocin, thioguanine, thiotepa, tobramycin, tretinoin, uracil, vinblastine, vincristine, vinorelbine... 

Figure 20. Two-pulse echo decay envelope of Cu(II) complexes of (a) bleomycin, (b) diethylenetriamine and imidazole, and (c) diethylenetriamine and pyrimidine. In traces a and b, one observes a modulation pattern arising from the interaction of Cu(ll) with the remote N of ligated imidazole. The respective magnetic fields and spectrometer frequencies are the following a, 3080 G, 9247 MHz b, 3195 G, 9251 MHz c, 2970 G, 9225 MHz. Lines indicating the periods were added by the authors. From [268], with permission.

---