Disturbance of the Conformation of DNA Hairpin Containing the 5′-GT-3′ Binding Site Caused by Zn(II)bleomycin-A₅ Studied through NMR Spectroscopy

Abstract

The antibiotics known as bleomycins constitute a family of natural products clinically employed for the treatment of a wide spectrum of cancers. These antibiotics have the ability to chelate a metal center, most commonly Fe(II), and cause site-specific DNA cleavage upon oxidation. Bleomycin therapy is a successful course of treatment for some types of cancers. However, the risk of pulmonary fibrosis as an undesirable side effect, limits the use of the antibiotics in cancer chemotherapy. Bleomycins are differentiated by their C-terminal, or tail, regions, which have been shown to closely interact with DNA. Pulmonary toxicity has been correlated to the chemical structure of the bleomycin C-termini through biochemical studies performed in mice. In the present study, we examined the binding of Zn(II)Bleomycin-A5 to a DNA hairpin of sequence 5′-CCAGTATTTTTACTGG-3′, containing the 5′-GT-3′ binding site. The results were compared to those from a previous study that examined the binding of Zn(II)Bleomycin-A2 and Zn(II)Peplomycin to the same DNA hairpin. We provide evidence that, as shown for DNA hairpins containing the 5′-GC-3′ binding site, Zn(II)BLM-A5 causes the most significant structural changes to the oligonucleotide.

Keywords

• DNA
• NMR
• pulmonary fibrosis
• anticancer drug
• structure–function