Solution structure of Fe(II)–azide–bleomycin derived from NMR data: transition from Fe(II)–bleomycin to Fe(II)–azide–bleomycin as derived from NMR data and structural calculations

Lehmann, Teresa; Li, Yang

doi:10.1007/s00775-012-0894-z

Cited by 4 publications

(1 citation statement)

References 21 publications

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“…determined that in the presence of azide the sixth ligand in Fe(II)BLM is released from coordination to allow azide binding [63]. With the aim of either supporting or not the coordination of a water molecule to the metal center in Fe(II)BLM, derived the solution structure of Fe(II)-azide-BLM was determined from NMR data [65,66]. The structural changes that take place on Fe(II)BLM upon azide binding were monitored by comparing the differences (root mean square deviations (RMSD)) between the experimentally determined proton-to-metal distances for Fe(II)BLM and Fe(II)-azide-BLM with those obtained from the calculated structures for Fe(II)BLM (structures 1 and 2) and Fe(II)-azide-BLM (Scheme 1).…”

Section: Metallo-blmsmentioning

confidence: 99%

Contributions of NMR to the Understanding of the Coordination Chemistry and DNA Interactions of Metallo-Bleomycins

Lehmann

Topchiy

2013

Molecules

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Abstract:Bleomycins are a family of glycopeptide antibiotics that have the ability to bind and degrade DNA when bound to key metal ions, which is believed to be responsible for their antitumor activity. Knowledge of the structures of metallo-bleomycins is vital to further characterize their mechanism of action. To this end, numerous structural studies on metallo-bleomycins have been conducted. NMR spectroscopy has had a key role in most of these studies, and has led to very important findings involving the coordination chemistry of metallo-bleomycins, and the details of many metallo-bleomycin-DNA spatial correlations for this important drug. This paper reviews the most important contributions of NMR to the bleomycin field.

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Section: Metallo-blmsmentioning

confidence: 99%

Contributions of NMR to the Understanding of the Coordination Chemistry and DNA Interactions of Metallo-Bleomycins

Lehmann

Topchiy

2013

Molecules

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NMR study of the effects of some bleomycin C-termini on the structure of a DNA hairpin with the 5′-GC-3′ binding site

et al. 2016

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The antibiotics known as bleomycins constitute a family of natural products clinically employed for the treatment of a wide spectrum of cancers. The drug acts as an antitumor agent by virtue of the ability of a metal complex of the antibiotic to cleave DNA. Bleomycins are differentiated by their C-terminal regions. Previous structural studies involving metal-bleomycin-DNA triads have allowed the identification of the bithiazole-(C-terminus substituent) segment in this molecule as the one that most closely interacts with DNA. Three different modes of binding of metallo-bleomycins to DNA (partial or total intercalation of the bithiazole unit between DNA bases, or binding to the minor groove) have been proposed in the literature. The therapeutic use of bleomycin is frequently associated with the development of pulmonary fibrosis. The severity of this side effect has been attributed to the C-terminus of the antibiotic by some researchers. The degree of pulmonary toxicity of bleomycin-A2 and -A5, were found to be higher than those of bleomycin-B2 and peplomycin. Since the introduction of Blenoxane to clinical medicine in 1972, attempts have been made at modifying the basic bleomycin structure at the C-terminus to improve its therapeutic index. However, the pharmacological and toxicological importance of particular C-termini on bleomycin remains unclear. The present study was designed to determine the effect of Zn(II)bleomycin-A2, -A5, -B2, and Zn(II)peplomycin on the structure of a DNA hairpin containing the 5′-GC-3′ binding site. We provide evidence that different Zn(II)bleomycins affect the structure of the tested DNA segment in different fashions.

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Interaction of Zn(II)bleomycin-A2 and Zn(II)peplomycin with a DNA hairpin containing the 5′-GT-3′ binding site in comparison with the 5′-GC-3′ binding site studied by NMR spectroscopy

et al. 2017

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Bleomycins are a group of glycopeptide antibiotics synthesized by Streptomyces verticillus that are widely used for the treatment of various neoplastic diseases. These antibiotics have the ability to chelate a metal center, mainly Fe(II), and cause site-specific DNA cleavage. Bleomycins are differentiated by their C-terminal regions. Although this antibiotic family is a successful course of treatment for some types of cancers, it is known to cause pulmonary fibrosis. Previous studies have identified that bleomycin-related pulmonary toxicity is linked to the C-terminal region of these drugs. This region has been shown to closely interact with DNA. We examined the binding of Zn(II)peplomycin and Zn(II)bleomycin-A2 to a DNA hairpin of sequence 5’-CCAGTATTTTTACTGG-3’, containing the binding site 5’-GT-3’, and compare the results with those obtained from our studies of the same MBLMs bound to a DNA hairpin containing the binding site 5’-GC-3’. We provide evidence that the DNA base sequence has a strong impact in the final structure of the drug-target complex.

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Solution structure of Fe(II)–azide–bleomycin derived from NMR data: transition from Fe(II)–bleomycin to Fe(II)–azide–bleomycin as derived from NMR data and structural calculations

Cited by 4 publications

References 21 publications

Contributions of NMR to the Understanding of the Coordination Chemistry and DNA Interactions of Metallo-Bleomycins

Contributions of NMR to the Understanding of the Coordination Chemistry and DNA Interactions of Metallo-Bleomycins

NMR study of the effects of some bleomycin C-termini on the structure of a DNA hairpin with the 5′-GC-3′ binding site

Interaction of Zn(II)bleomycin-A2 and Zn(II)peplomycin with a DNA hairpin containing the 5′-GT-3′ binding site in comparison with the 5′-GC-3′ binding site studied by NMR spectroscopy

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