Chemistry of bleomycin. XIX. Revised structures of bleomycin and phleomycin.

Takita, Tomohisa; Muraoka, Yasuhiko; Nakatani, Tokuji; Fujii, Akio; Umezawa, Yōji; Naganawa, Hiroshi; Umezawa, Hamao

doi:10.7164/antibiotics.31.801

Cited by 168 publications

(70 citation statements)

References 7 publications

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“…Its early structural assignment, which contained a b-lactam, was revised to its correct structure in 1978 [17] and its spectroscopically-derived absolute configuration was confirmed in our synthetic efforts. [18] Bleomycin A 2 is thought to exert its biological effects through DNA binding and degradation, a process that is metal-ion and oxygen dependent.…”

Section: Introductionmentioning

confidence: 99%

Bleomycin: Synthetic and Mechanistic Studies

Boger

Cai

1999

Angew. Chem. Int. Ed.

144

153

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The subtleties of the structure and function of bleomycin A (1), a clinically employed antitumor agent that derives its biological properties through the sequence-selective cleavage of DNA in a process that is dependent on the metal ion and O , have been unraveled in a stepwise manner. Systematic modifications in the structure of 1 enabled many of the subtle functional roles of the individual subunits and their substituents in the efficiency, selectivity, and preference (double strand versus single strand) of DNA cleavage to be elucidated.

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Section: Introductionmentioning

confidence: 99%

Bleomycin: Synthetic and Mechanistic Studies

Boger

Cai

1999

Angew. Chem. Int. Ed.

144

153

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“…While the chemical structure of BLM was reported as early as 1978 [21], the tertiary structure of BLMs and its mode of action have not yet been entirely elucidated. There is continuing uncertainty concerning the exact ligands and coordination structure around the metal ions in various BLMs.…”

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confidence: 99%

Structures of Cobalt(III)‐Pepleomycin and Cobalt(III)‐Deglycopepleomycin (green forms) Determined by NMR Studies

Caceres‐Cortes

Sugiyama

Ikudome

et al. 1997

European Journal of Biochemistry

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Pepleomycin (PEP) is a metalloglycopeptide that has stronger anticancer activity and less pulmonary toxicity than bleomycin (BLM). PEP, like BLM, exerts its action by binding to and degrading DNA in the presence of oxygen and certain metals. Obtaining detailed structural information of PEP and PEP-DNA complexes is crucial to understanding its anticancer activity. The structures of two green forms of cobalt-PEP species, HOT-Co(II1)-PEP (denoted CoPEP) and deglycosylated HOT-Co(II1)-PEP (denoted CodPEP) have been obtained by NOE restrained refinements. Earlier studies of the related H0;-Co(II1)-BLM A, proposed that two chiral conformers (form A or B) could exist with either the /I-aminoalanine primary amine (A,NH,) or the mannose carbamoyl nitrogen (M,NH,) as the axial ligand. Analysis of our NOESY data shows convincingly that form A is the most probable conformer with the mannose carbamoyl M,NH, and the p-aminoalanine primary amine A,NH, as the axial ligands in CoPEP and CodPEP, respectively. The NOE cross-peaks resulting from the interactions between the N-terminus (i.e., the metalbinding domain) and the C-terminus of CoPEP and CodPEP have similar patterns, suggesting that they both adopt compact structures with the bithiazole group folded back over the N-terminus.Keywords : pepleomycin ; deglycosylated pepleomycin ; DNA ; two-dimensional NMR ; solution structure.Bleoniycins (BLMs) are a group of structurally related metalloglycopeptide antitumor antibiotics [ I]. The structure of BLM ( Fig. 1) is commonly divided into three functional domains. The N-terminus, or metal-binding domain, is responsible for metal binding, oxygen bindinglactivation, and DNA binding [2]. The disaccharide participates in metal-ion binding [3, 41 and may additionally be involved in cell surface recognition [5]. The Cterminus, or DNA-binding domain, is composed of a bithiazole group plus a substituent and participates in DNA binding [6]. BLMs differ from one another in their C-terminal substituents [7] and show varying biological activity.Presently, a mixture of BLMs (mainly of BLM-A, and BLM-B2) are clinically used for the treatment of certain cancers including squamous cell carcinomas, testicular tumors and malignant lymphomas [8, 91. The most adverse side effect is pulmonary fibrosis. To produce a more potent and less toxic drug, about 300 derivatives of BLM have been prepared and screened [lo]. Among these is pepleomycin, PEP, (Fig. 1) The therapeutic effects of BLM and PEP are believed to derive from their ability to bind to and selectively degrade DNA [15, 161, and possibly RNA [17], in the presence of molecular oxygen and certain metal ions. BLM was first isolated as the 1 : 1 cupric-BLM complex [l], but the ferrous-BLM complex has been proposed as the biologically active species [18]. Fe(I1)-BLM reacts with molecular oxygen to produce an activated form of the drug (reactions 1 and 2) which binds to DNA and mediates DNA strand scission by abstracting the C4' hydrogen of the deoxyribose of a pyrimidine nucleotide adjacent to guan...

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“…However, other workers have shown that whereas strains of E. coli lacking post-replication repair are more sensitive to BLM than wild-type strains, mutants deficient in excision repair functions are no more sensitive to the drug than repair-proficient strains (Yamagami et al, 1974;Otsuji et al, 1978;Yamamoto & Hutchinson, 1979). Furthermore, the phleomycins, which show a close structural similarity to BLM (Takita et al, 1972) and also induce strand scission in DNA (Grigg, 1969;Farrel & Reiter, 1973), are more lethal to r e d , recB or recA recB double mutants than to wild-type strains, whereas mutants that are uvrA, uvrB, uvrC, uvrD or polA are no more sensitive to the drug (Nakayama, 1975) than are wild-type strains. Hence, the repair of DNA strand breaks mediated by BLM or phleomycins would seem to involve post-replication repair processes rather than excision repair functions.…”

Section: Discussionmentioning

confidence: 99%

Plasmid R46-mediated Protection Against Bleomycin is polA+-dependent

Attfield

Pinney

1982

Microbiology

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Strains of Escherichia coli deficient in post-replication recombination repair were more sensitive to bleomycin than wild-type, repair-proficient strains. Mutants lacking excision repair functions were no more sensitive to bleomycin than the wild-type strains, indicating that this pathway is not involved in the repair of bleomycin-damaged DNA. Plasmid R46 not only protected repair-proficient strains but also those with recB, re&, uvrA or lig genotypes, suggesting that R46 protection against bleomycin is independent of these host repair functions. However, R46 protection was abolished in recA or polA strains, indicating that these gene functions are necessary for plasmid-mediated protection. It is suggested that protection may be due to a recA+-dependent interaction of a plasmid-encoded product with host DNA polymerase I, resulting in an increase in the DNA repair capacity of cells.

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Chemistry of bleomycin. XIX. Revised structures of bleomycin and phleomycin.

Cited by 168 publications

References 7 publications

Bleomycin: Synthetic and Mechanistic Studies

Bleomycin: Synthetic and Mechanistic Studies

Structures of Cobalt(III)‐Pepleomycin and Cobalt(III)‐Deglycopepleomycin (green forms) Determined by NMR Studies

Plasmid R46-mediated Protection Against Bleomycin is polA+-dependent

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