A 13C nmr and esr study on the structure of the different forms of the cobalt-bleomycin A2 complex

Vos, Cornelis M.; Westera, G.; Schipper, Dick

doi:10.1016/s0162-0134(00)80119-1

Cited by 25 publications

(9 citation statements)

References 16 publications

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“…¶ 1 1 In the first two complexes, it is clear that intermolecular complexation cannot be distinguished. These results and interpretations agree with those ofother studies showing bithiazole interaction with the metal in Cu(II)Blm, Co(II)Blm, and Mn(II)Blm (17)(18)(19). GSH competes with the bithiazole moiety of excess Blm for a binding site on NO-Fe(II)Blmn (Fig.…”

Section: Discussionsupporting

confidence: 92%

Interactions among iron(II) bleomycin, Lewis bases, and DNA.

Antholine¹,

Petering²,

Saryan³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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The interaction of sulfur-containing ligands with complexes of Fe(il) bleomycin [Fe(IJ)Blm] was investigated by comparing DNA strand-scission activity with the structural characteristics of the complex. The bithiazole ring of excess BIm can form intermolecular complexes with Fe(II)Blm and with NO-Fe(II)Blm, and the-bithiazole groups of CO-Fe(II)Blm interact with the metal center. This binding can be reversed by glutathione. CO-Fe(II)Blm -binds to poly(dA-dT)-poly(dA-dT) via its bithiazole group to change the environment of the Fe2+ ion. Glutathione binds to the CO-Fe(II)Blm-poly(dA-dT)-poly(dA-dT) complex under conditions in which it stimulates DNA strand scission by Fe(II)Blm.The antitumor agent bleomycin (Blm) in its clinical formulation is primarily a mixture of the two closely related glycopeptides, Blm A2 and Blm B2 (1, 2). It has been suggested that the activity of Blm results from its reaction with DNA to cleave the backbone (3-5). The mechanism ofthis cleavage apparently involves the initial formation of Fe(II)Blm and then a redox reaction between the iron center and oxygen to produce Fe(III)Blm and a reactive oxygen species such as the hydroxyl radical (6-9). Further, it has been suggested that the reaction in cells uses FeBlm as a redox catalyst for the. reduction of02 to an activated form by thiols (9-11). Recent poly(dA-dT)-poly(dA-dT) (0.08 mM in thymine bases and 0.16 mM in total bases) was dissolved in 50 mM sodium phosphate, pH 7.0; this solution was incubated with unchelated Blm for 1 min at 370 C. The strand-scission reaction was initiated by addition ofeither Fe(NH4)2(SO4)2 or Fe(III)Blm/cysteine and was permitted to continue for 15 min at 370C. GSH and cysteine were added to the incubation mixture immediately after initiation of the reaction.Preparation of Samples for 1H NMR Spectroscopy. Coin-.plexes of Fe2' and Blm were prepared in the presence and absence of additional ligands under anaerobic conditions as described (14). Solutions of Blm and Fe(NH4)2(SO4)2 were prepared in 2H20/0. 1 M NaCl/dithionite (15). The pD values were maintained in the 7.5-8.3 range. The solution was transferred under nitrogen to a 5-mm NMR tube, which then was capped and sealed with vacuum grease and parafilm. The 'H NMR spectrum of each sample was recorded at 25°C immediately after preparation on a Nicolet NT-150 spectrometer with a 5-mm proton probe. The deuterium of the solvent was used as the internal lock signal and the chemical shifts were referenced to external tetramethylsilane. Each spectrum required accumulation ofabout 500 free induction decays with a recycle time of 5 sec. RESULTS DNA Strand Scission in the Presence of Blm and Iron. Less than 5% of double-stranded DNA is degraded to acid-soluble

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Section: Discussionsupporting

confidence: 92%

Interactions among iron(II) bleomycin, Lewis bases, and DNA.

Antholine¹,

Petering²,

Saryan³

et al. 1981

Proc. Natl. Acad. Sci. U.S.A.

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“…However, NMR studies by Oppenheimer et al32,33 on Zn(II)-BLMs and Fe(II)-BLM-CO resulted in the proposal of an alternative structure, analogous to the one proposed by 31 for Co(III)-BLM. In this proposed structure, the pyrimidine and imidazole ligands have a cis relationship, creating a nine-membered chelate ring.…”

Section: Metal Complexes Of Blmmentioning

confidence: 95%

“…In Scheme 9a the activated BLM mediates a hydrogen atom abstraction from the C47 carbon to produce the 47-carbon radical. The 47-radical may then undergo a radical rebound mechanism, in analogy with proposals of Groves and co-workers for cyt P450 systems,59,122 to produce 30. Alternatively (Scheme 9b), the radical could be oxidized by "Feni-OH" to produce a C47 carbonium ion, which could then add H20 to produce the same intermediate 30. This intermediate 30 can then collapse via a oneor two-step sequence to produce 31 and free base. The modified sugar residue 31 in the presence of OHcould undergo strand scission to produce 57-phosphate termini.…”

Section: B Proposed Mechanism For Base Releasementioning

confidence: 99%

Mechanisms of bleomycin-induced DNA degradation

Stubbe¹,

Kozarich²

1987

Chem. Rev.

895

643

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“…Unfortunately, this metabolite lacks the disaccharide and the DNAbinding domain and, therefore, may not represent the ligand environment for the full BLM. NMR spectroscopy has been used to investigate the structure of the metal-binding domain and to determine the overall conformations of various metallobleomycins, including Cu-, Fe-, Zn-and CoBLM [3,4,[23][24][25][26][27]. Nonetheless, proton NMR spectroscopy is of limited value for the study of Cu(I1)-BLM and Fe(I1)-BLM complexes because of paramagnetic effects.…”

mentioning

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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A 13C nmr and esr study on the structure of the different forms of the cobalt-bleomycin A2 complex

Cited by 25 publications

References 16 publications

Interactions among iron(II) bleomycin, Lewis bases, and DNA.

Interactions among iron(II) bleomycin, Lewis bases, and DNA.

Mechanisms of bleomycin-induced DNA degradation

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

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