Identification of a key structural feature of cobalt(III)-bleomycins: An exogenous ligand (e.g. Hydroperoxide) bound to cobalt

Chang, Chien-Hsing; Dallas, Jerry L.; Meares, Claude F.

doi:10.1016/0006-291x(83)91056-2

Cited by 31 publications

(26 citation statements)

References 27 publications

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“…A number of laboratories prepared Co(III)-BLMs from Co(II), 02, and BLM; however, it was not until recently that the complex mixture of products produced were separated and partially characterized31, 124,127,130 (Scheme 11, Table XI). The Co(III)-BLMs are isolable with CM-Sephadex (ammonium formate elution) followed by reversed-phase HPLC.…”

Section: Co(iii)-blmmentioning

confidence: 99%

Mechanisms of bleomycin-induced DNA degradation

Stubbe¹,

Kozarich²

1987

Chem. Rev.

895

643

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Section: Co(iii)-blmmentioning

confidence: 99%

Mechanisms of bleomycin-induced DNA degradation

Stubbe¹,

Kozarich²

1987

Chem. Rev.

895

643

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“…CoBLM A2 green (HOO-CoBLM) has an octahedral coordination environment (Figure , N indicate ligands) with the primary amine of β-aminoalanine and a hydroperoxide as the axial ligands. This complex cleaves DNA only in the presence of light and does so with the same sequence and chemical specificity as the FeBLMs. − These similarities, its diamagnetic character, and exchange inert ligands made it the metallo-BLM of choice for investigation by 2D NMR methods. − ,− Most importantly, CoBLM A2 green is believed to be an excellent analog of the activated BLM, HOO-FeBLM, and thus the model structure obtained with this form of metallo-BLM is thought to be indicative of the FeBLM system. ,, During the synthesis of HOO-CoBLM, CoBLM A2 brown, with an axial H 2 O or HO - ligand, is also generated. − It is also diamagnetic, and its H 2 O or HO - axial ligand is exchangeable with solvent . In contrast to HOO-CoBLM, it does not catalyze cleavage of DNA …”

Section: Introductionmentioning

confidence: 99%

Structural Characterization of Co·Bleomycin A2 Brown: Free and Bound to d(CCAGGCCTGG)

Lui

Vanderwall

et al. 1997

J. Am. Chem. Soc.

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A model for the structure of the aquated form of cobalt bleomycin (H2O-CoBLM or CoBLM A2 brown), free and bound to d(CCAGGCCTGG)2 (1) is reported based on molecular modeling using the constraints obtained from 2D NMR studies. CoBLM A2 brown has a chiral organization of its ligands, including the axial primary amine of β-aminoalanine, identical to the hydroperoxide form of cobalt BLM (HOO-CoBLM or CoBLM A2 green). H2O-CoBLM forms a 1:1 complex with 1 with a K d of 2 × 10-6 M which is in slow exchange on the NMR time scale. The complex exhibits 44 intermolecular NOEs and 56 intramolecular NOEs within H2O-CoBLM itself. Molecular modeling reveals that H2O-CoBLM's mode of binding, basis for sequence specificity, and chemical specificity are almost identical to that previously reported for HOO-CoBLM (Wu, W.; Vanderwall, D. E.; Turner, C. J.; Kozarich, J. W.; Stubbe, J. J. Am. Chem. Soc. 1996, 118, 1281−1294). The bithiazole tail is inserted from the minor groove 3‘ to C6 and the terminal thiazolium ring is well stacked between the bases G14 and G15, while the penultimate thiazolium ring is only partially stacked between the bases of C6 and C7. The basis for sequence specificity involves hydrogen-bonding interactions between the 4-amino group and N3 of the pyrimidine of BLM and the N3 and 2-amino group of G5 of DNA, forming an unusual base triple. Molecular modeling further reveals that the oxygen of the axial H2O ligand is 2.7 Å from the 4‘ H of C6, the site of cleavage of iron BLM and light-activated cleavage by HOO-CoBLM. Preliminary studies of H2O-CoBLM with d(CCAGTACTGG) (4) and d(GGAAGCTTCC) (2) are also reported.

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“…Facilitating structural studies, HOO-Co(III)⅐bleomycin ''green'' ( Fig. 1) (15) constitutes a stable structural analogue of O 2 activated Fe(II)⅐bleomycin, HOO-Fe(III)⅐bleomycin, that interacts with the same DNA site-selectivity (16)(17)(18)(19)(20) but requires photoactivation to cleave DNA. From 2D NMR derived models reported for DNA-bound HOO-Co(III)⅐bleomycin, the bithiazole is intercalated and the pyrimidinyl ring of the metal-binding domain interacts with the guanine of the 5Ј-GC site via the minor groove (21)(22)(23)(24)(25).…”

mentioning

confidence: 99%

Crystal structure of DNA-bound Co(III)·bleomycin B ₂ : Insights on intercalation and minor groove binding

Goodwin

Lewis

Long

et al. 2008

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

108

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Bleomycins constitute a widely studied class of complex DNA cleaving natural products that are used to treat various cancers. Since their first isolation, the bleomycins have provided a paradigm for the development and discovery of additional DNA-cleaving chemotherapeutic agents. The bleomycins consist of a disaccharide-modified metal-binding domain connected to a bithiazole/Cterminal tail via a methylvalerate-Thr linker and induce DNA damage after oxygen activation through site-selective cleavage of duplex DNA at 5-GT/C sites. Here, we present crystal structures of two different 5-GT containing oligonucleotides in both the presence and absence of bound Co(III)⅐bleomycin B 2. Several findings from our studies impact the current view of bleomycin binding to DNA. First, we report that the bithiazole intercalates in two distinct modes and can do so independently of well ordered minor groove binding of the metal binding/disaccharide domains. Second, the Co(III)-coordinating equatorial ligands in our structure include the imidazole, histidine amide, pyrimidine N1, and the secondary amine of the ␤ aminoalanine, whereas the primary amine acts as an axial ligand. Third, minor groove binding of Co(III)⅐bleomycin involves direct hydrogen bonding interactions of the metal binding domain and disaccharide with the DNA. Finally, modeling of a hydroperoxide ligand coordinated to Co(III) suggests that it is ideally positioned for initiation of C4-H abstraction.antitumor ͉ DNA-binding ͉ HOO-Co(III) bleomycin T he bleomycins are a family of glycopeptide-derived antitumor natural products first isolated from Streptomyces verticillus by Umezawa (1). Bleomycins are used to treat lymphomas (2, 3) and testicular cancers (4), most often in combination therapies. The clinical efficacy of the bleomycins is thought to derive from their ability to mediate single-and double-strand DNA cleavage (5, 6) resulting from Fe 2ϩ and O 2 -dependent (7) C4Ј-H abstraction from pyrimidine nucleotides (8) contained within 5Ј-GT/C dinucleotide sites (9). Of the DNA lesions formed, double-strand DNA cleavage is thought to be most relevant to the cytotoxicity of bleomycin. Although DNA is the generally accepted locus of drug activity, O 2 -activated Fe(II)⅐bleomycin also mediates the selective cleavage of RNA (10), and Cu(I)⅐bleomycin is capable of cleaving DNA (11); however, the in vivo relevance of this alternative nucleic acid target and metal ion remain to be fully determined.The metallobleomycins have served as an important paradigm for nucleic acid-targeted drug design (12,13); and yet, despite extensive study over the past 40 years, fundamental aspects of their activity have yet to be fully defined including the role of particular DNA-binding modes on drug activity and the mechanism of double-strand DNA cleavage (14). Facilitating structural studies, HOO-Co(III)⅐bleomycin ''green'' (Fig. 1) (15) constitutes a stable structural analogue of O 2 activated Fe(II)⅐bleomycin, HOO-Fe(III)⅐bleomycin, that interacts with the same DNA site-selectivity (16-20)...

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Identification of a key structural feature of cobalt(III)-bleomycins: An exogenous ligand (e.g. Hydroperoxide) bound to cobalt

Cited by 31 publications

References 27 publications

Mechanisms of bleomycin-induced DNA degradation

Mechanisms of bleomycin-induced DNA degradation

Structural Characterization of Co·Bleomycin A2 Brown: Free and Bound to d(CCAGGCCTGG)

Crystal structure of DNA-bound Co(III)·bleomycin B ₂ : Insights on intercalation and minor groove binding

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Identification of a key structural feature of cobalt(III)-bleomycins: An exogenous ligand (e.g. Hydroperoxide) bound to cobalt

Cited by 31 publications

References 27 publications

Mechanisms of bleomycin-induced DNA degradation

Mechanisms of bleomycin-induced DNA degradation

Structural Characterization of Co·Bleomycin A2 Brown: Free and Bound to d(CCAGGCCTGG)

Crystal structure of DNA-bound Co(III)·bleomycin B 2 : Insights on intercalation and minor groove binding

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Crystal structure of DNA-bound Co(III)·bleomycin B ₂ : Insights on intercalation and minor groove binding