Preparation, Structure Determination and Cytotoxicity of the Pd<sup>II</sup>·Bleomycin A2 Complex

Papakyriakou, Athanasios; Bratsos, Ioannis; Katsarou, Maria E.; Katsaros, Nikos

doi:10.1002/ejic.200400034

Cited by 2 publications

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“…BLM provides five or six ligands for binding to the iron. Because no crystal structure exists, current knowledge of the Fe−BLM structure is based on spectroscopy, − molecular dynamics modeling, density functional calculations, , and studies on BLM complexes with Co, − Cu, , and other metals. − All studies agree on five nitrogen-based ligands (indicated in bold in Figure ). The four equatorial ligands are generally accepted to be an imidazole nitrogen, a deprotonated amide, a pyrimidine nitrogen, and the secondary amine functionality of the β-aminoalanine.…”

Section: Introductionmentioning

confidence: 99%

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

et al. 2006

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Bleomycin (BLM), a glycopeptide antibiotic chemotherapy agent, is capable of single- and double-strand DNA damage. Activated bleomycin (ABLM), a low-spin Fe(III)-OOH complex, is the last intermediate detected prior to DNA cleavage following hydrogen-atom abstraction from the C-4' of a deoxyribose sugar moiety. The mechanism of this C-H bond cleavage reaction and the nature of the active oxidizing species are still open issues. We have used kinetic measurements in combination with density functional calculations to study the reactivity of ABLM and the mechanism of the initial attack on DNA. Circular dichroism spectroscopy was used to directly monitor the kinetics of the ABLM reaction. These experiments yield a deuterium isotope effect, kH/kD approximately 3 for ABLM decay, indicating the involvement of a hydrogen atom in the rate-determining step. H-atom donors with relatively weak X-H bonds accelerate the reaction rate, establishing that ABLM is capable of hydrogen-atom abstraction. Density functional calculations were used to evaluate the two-dimensional potential energy surface for the direct hydrogen-atom abstraction reaction of the deoxyribose 4'-H by ABLM. The calculations confirm that ABLM is thermodynamically and kinetically competent for H-atom abstraction. The activation and reaction energies for this pathway are favored over both homolytic and heterolytic O-O bond cleavage. Direct H-atom abstraction by ABLM would generate a reactive Fe(IV)=O species, which would be capable of a second DNA strand cleavage, as observed in vivo. This study provides experimental and theoretical evidence for direct H-atom abstraction by ABLM and proposes an attractive mechanism for the role of ABLM in double-strand cleavage.

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Section: Introductionmentioning

confidence: 99%

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

et al. 2006

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The influence of steric effects on intramolecular secondary bonding interactions; cytotoxicity in gold(iii) bithiazole complexes

et al. 2013

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The reaction of two sterically different bithiazole ligands with gold(III) was investigated. Our results show that, depending on the ligand used, different coordination geometries around the gold(III) center were achieved. Where sterically unhindered 4bt ligand was used, regular square-planar compound [Au(4bt)Cl2][AuCl4] (1) is isolated, while in the case of sterically hindered dm4bt ligand, the interplay between the steric effect and the intramolecular secondary bonding interaction leads to the formation of disordered square-pyramidal geometry in [Au(dm4bt)Cl3] (2). Furthermore, the steric influence of the methyl group in the ligand plays an important role in the cytotoxicity of the compound in different cultures. Interestingly, compound 1 is more potent to kill a breast cancer cell line than cisplatin (13 times), and its cytotoxicity arises from the cationic part, [Au(4bt)Cl2](+).

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Preparation, Structure Determination and Cytotoxicity of the Pd^II·Bleomycin A2 Complex

Cited by 2 publications

References 72 publications

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

The influence of steric effects on intramolecular secondary bonding interactions; cytotoxicity in gold(iii) bithiazole complexes

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Preparation, Structure Determination and Cytotoxicity of the PdII·Bleomycin A2 Complex

Cited by 2 publications

References 72 publications

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

Direct Hydrogen-Atom Abstraction by Activated Bleomycin: An Experimental and Computational Study

The influence of steric effects on intramolecular secondary bonding interactions; cytotoxicity in gold(iii) bithiazole complexes

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Preparation, Structure Determination and Cytotoxicity of the Pd^II·Bleomycin A2 Complex