Bleomycin isolation

The phleomycin, bleomycin and related families are widespectrum antibiotics containing the pyrimidine (987) in addition, they have antineoplastic activity and bleomycin is already in clinical use for certain tumours. They were isolated about 1956 from Streptomyces verticillus, and in addition to the pyrimidine portion the molecules contain an amide part (R ) and a complicated part (R ) consisting of polypeptide, an imidazole, two sugars, a bithiazole and a polybasic side chain which can vary widely phleomycin and bleomycin differ by only one double bond in the bithiazole section (78MI21303). The activity of such antibiotics is increased by the addition of simple heterocycles (including inter alia pyrimidines and fused pyrimidines) and other amplifiers (82MI21300). 

Bleomycin (BLM) was first isolated as a copper complex from a culture of Streptomyces verticillus. Since then numerous analogs have been prepared by modifying the conditions of fermentation. Bleomycins (114, bleomycin A2) are used clinically in combination cancer chemotherapy for the treatment of head and neck cancer, certain lymphomas, and testicular cancer (555). 

Methanoserine or cleonine 106 has been isolated from cleomycin 107 a, an antibiotic from the bleomycin-phleomycin group, which is different from bleomycin 107b only in its threonine moiety [38]. This amino-(1-hydroxycyclo-propyl)acetic acid is located in the place of the threonine, Eq. (42). 

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-... 

Bleomycin is a mixture of glycopeptide antibiotics isolated from cultures of Streptomyces verticillus, used for its anticancer activity. The major component (55-70%) of the mixture... 

In isolated rat nuclei, SOD inhibits bleomycin-induced membrane peroxidation, but has no effect on bleomycin-catalysed DNA scission [57]. Thus, it may be possible to use iron chelators to reduce the toxic extracellular side effects of these drugs, whilst leaving the intracellular therapeutic mode of action unaltered. In fact, it has been demonstrated that the cardiotoxicity of adriamycin can be inhibited by the chelating agent ICRF-187 [60],... 

The bleomycins (BLMs), such as BLM A2, B2, and AS, are a family of antitumor glycopeptide-derived antibiotics isolated from Streptomyces verticillus <2003B9731, 2002JBC2311>. 

Tallysomycins A and B, first isolated from fermentation broths of Streptoalloteichus hindustanus, are glycopeptide-derived antitumor antibiotics structurally related to the bleomycins <20010L2811>. 

The bleomycins are a group of glycopeptides isolated from Streptomyces verticillus as copper complexes. They have attracted much attention because, in addition to having antimicrobial and antiviral properties, they are also important in the treatment of a number of tumours, including Hodgkin s disease. Some 200 bleomycins have now been identified, although the main component of the clinical drug is bleomycin Bleomycin requires a metal ion. The Fe complex is... 

Bleomycin was isolated from the culture filtrate of Streptomyces verticillus by ion exchange resin adsorption, alumina and Sephadex column chromatography. Bleomycin thus obtained was a mixture of more than 10 components, which can be separated on a CM-Sephadex column by elution with a linear gradient of ammonium formate5) (see Fig. 1). Later, it was found that they are different from one another in... 

Fig. 1. CM-Sephadex C-2S chromatography of bleomycin complex isolated from the cultured broth...

After clarification of the structural relation between BLM and PHM, the nephrotoxicity of PHM described earlier was reinvestigated. The PHM used for the toxicity tests was a mixture which contained appreciable amounts of BLMs B4 and B6. Bleomycins B4 and B6 showed strong nephrotoxicity in the dog. The BLM mixture isolated from the BLM fermentation contained only a small amount of BLMs B4 and B6 (Fig. 1). The above-mentioned facts suggested that the nephrotoxicity of PHM found earlier was not an intrinsic propertiy of PHM in general, but was due to the specific toxic components. To prove this, an artificial PHM, which has the same terminal amine as that of BLM A2, was prepared by fermentation added with (3-aminopropyl) dimethylsulfonium chloride as a precursor for the terminal amine30 and was examined for the toxicity. This artificial PHM showed no nephrotoxicity like BLM A2. Thus, it has been proved that the nephrotoxicity of PHM in the earlier experiment is not a property of PHM in general, but is due to the specific toxic component. 

Bleomycin, which is isolated frOm the fermentation broth of Streptomyces verticillus, is the blue equimolar Cu (Il)-complex. The copper originates from an inorganic cupric salt added to the fermentation medium. Without addition of the copper, production of BLM is markedly reduced. The copper seems to be essential for the biosynthesis of BLM (II-7). 

The resonance Raman spectrum of HOO-Coin(bleomycin) includes vO-OH at 828/784 cirT 1 (160/180).338 Matrix-isolated Co(MPyTPP), where MPyTPP = meso-triphenyl(4-pyridyl)-porphyrinato, and 02 form an unstable 5-coordi-nate 02-adduct (v02 1286 cm-1) and a more stable 6-coordinate species (additional coordination by a py group of adjacent Co(MPyTPP)) with v02 at 1160 cm-1 (1103 cm 1 for lsO).339... 

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