Cobalt(III) complex of pseudotetrapeptide A of bleomycin

Dabrowiak, James C.; Tsukayama, Masao

doi:10.1021/ja00415a023

Cited by 33 publications

(27 citation statements)

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“…4 B and 5C). These upfield chemical shifts are consistent with the results obtained for the hydrolysis product of Co(II1)-BLM A, [23], which lacked the sugars mannose and gulose (A,NH, = 4.4h.3 ppm at pD 2.1). This significant chemical-shift difference of the A, NH, protons suggests that in CodPEP, this amine is involved in ligand binding to cobalt while in CoPEP, this amine is not bound to cobalt.…”

Section: Nmr Analysis Of Copep and Codpepsupporting

confidence: 89%

“…4 B and 5C). These upfield chemical shifts are consistent with the results obtained for the hydrolysis product of Co(II1)-BLM A, [23], which lacked the sugars mannose and gulose (A,NH, = 4.4h.3 ppm at pD 2.1). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 134 182 112 78 141 183 40.5 414 74 60 222 57 36 156 15 84 53 39 60 120 195 48 1695 66 699 60 246 57 24 105 39 51 51 357 1482 87 126 63 45 120 51 225 63 75 54 120 51 18 93 18 60 12 18 33 42 222 30 1092 39 375 24 279 18 21 84 57 21 21 213 This significant chemical-shift difference of the A, NH, protons suggests that in CodPEP, this amine is involved in ligand binding to cobalt while in CoPEP, this amine is not bound to cobalt.…”

Section: A-hpsupporting

confidence: 89%

“…Several studies which examined the coordination of BLM A, to Co(iI1) [23,24,361 concluded that five nitrogen donor atoms from BLM A, bind to cobalt. These include the primary and secondary amines of A, the pyrimidine N5 of P, the imidazole N1 and the amide nitrogens of H. These five nitrogens, together with a hydroperoxide group, adopt a square bipyramidal geometry around cobalt with the primary amine of A and the hydroperoxide group in the axial positions and the other nitrogens making up the equatorial plane around cobalt (Fig.…”

Section: Nmr Analysis Of Copep and Codpepmentioning

confidence: 99%

“…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%

“…Nonetheless, proton NMR spectroscopy is of limited value for the study of Cu(I1)-BLM and Fe(I1)-BLM complexes because of paramagnetic effects. This has prompted the NMR study of other metal-BLM complexes such as Zn(I1)-BLM [28,291 and Co(II1)-BLM [23,241, which are diamagnetic.…”

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confidence: 99%

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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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“…4 B and 5C). These upfield chemical shifts are consistent with the results obtained for the hydrolysis product of Co(II1)-BLM A, [23], which lacked the sugars mannose and gulose (A,NH, = 4.4h.3 ppm at pD 2.1). This significant chemical-shift difference of the A, NH, protons suggests that in CodPEP, this amine is involved in ligand binding to cobalt while in CoPEP, this amine is not bound to cobalt.…”

Section: Nmr Analysis Of Copep and Codpepsupporting

confidence: 89%

“…4 B and 5C). These upfield chemical shifts are consistent with the results obtained for the hydrolysis product of Co(II1)-BLM A, [23], which lacked the sugars mannose and gulose (A,NH, = 4.4h.3 ppm at pD 2.1). 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 134 182 112 78 141 183 40.5 414 74 60 222 57 36 156 15 84 53 39 60 120 195 48 1695 66 699 60 246 57 24 105 39 51 51 357 1482 87 126 63 45 120 51 225 63 75 54 120 51 18 93 18 60 12 18 33 42 222 30 1092 39 375 24 279 18 21 84 57 21 21 213 This significant chemical-shift difference of the A, NH, protons suggests that in CodPEP, this amine is involved in ligand binding to cobalt while in CoPEP, this amine is not bound to cobalt.…”

Section: A-hpsupporting

confidence: 89%

Section: Nmr Analysis Of Copep and Codpepmentioning

confidence: 99%

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confidence: 99%

mentioning

confidence: 99%

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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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Bleomycin: Untersuchungen zu Synthese und Wirkungsmechanismus

Boger¹,

Cai²

1999

Angewandte Chemie

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Stückweise entschlüsselt wurden die Feinheiten der Struktur und Funktion von Bleomycin A2 1, einem klinisch eingesetzten Antitumormittel, das seine biologische Wirkung über die Metallionen‐ und O2‐abhängige, sequenzselektive Spaltung von DNA ausübt. Durch systematisches Modifizieren der Struktur von 1 war es möglich, die subtilen funktionellen Rollen der einzelnen Molekülteile und ihrer Substituenten für Effizienz, Selektivität und Präferenz (Doppelstrang‐ gegenüber Einzelstrang‐DNA) der DNA‐Spaltung aufzuklären.

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