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

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• 作者：Teresa E. Lehmann ; Sally A. Murray…
• 关键词：DNA ; NMR ; Structure–function ; Anticancer drug ; Pulmonary fibrosis
• 刊名：JBIC Journal of Biological Inorganic Chemistry
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：22
• 期：1
• 页码：121-136
• 全文大小：
• 刊物类别：Biomedical and Life Sciences
• 刊物主题：Biochemistry, general; Microbiology;
• 出版者：Springer Berlin Heidelberg
• ISSN：1432-1327
• 卷排序：22

文摘

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.