Effects of DNA Binding on the Structure of Bleomycin Analogs and DNA Hairpins Examined by NMR Spectroscopy.

摘要

Bleomycins are antitumor antibiotics that are clinically used for the treatment of various cancers. These antibiotics have the ability to chelate a metal center and cause site-specific DNA cleavage. Bleomycins have been identified to interact with 5'-G(pyrimidine)-3' regions in DNA sequences. Although bleomycins are successfully used in treatments for some types of cancers, they are known to cause pulmonary fibrosis. Previous studies have identified that the bleomycin lung toxicity is related to the C-terminal region of the molecule, which differentiate bleomycin analogs. This region has been shown to closely interact with DNA in metal-bleomycin-DNA studies. A few binding modes have been proposed for these metal-bleomycin-DNA complexes (total intercalation, partial intercalation, and groove binding), but an exact mechanism has not been established. Clinically, bleomycins are administered as a mixture known as Blenoxane, but extensive research is still underway to eliminate the pulmonary toxicity side effects and improve its therapeutic index. Previous studies have identified that bleomycins-A 2 and -A5 have a higher degree of toxicity than bleomycin-B 2 and peplomycin. Even though bleomycin-A2 is more toxic than bleomycin-B2, it has been shown to have a higher antitumor activity. Extensive research is necessary to understand the exact role of the C-terminal region and its direct relationship to pulmonary toxicity. Previous studies have used different metallo-bleomycins and DNA fragments in their investigation of DNA binding by bleomycin, making it difficult to make comparisons between the results derived from them. Herein, the binding interactions of four different metallo-bleomycin complexes with DNA hairpins containing either the 5'-GC-3' or 5'-GT-3' binding site have been examined through nuclear magnetic resonance spectroscopy. Evidence is provided that the Drug-DNA interactions affect both the structures of the DNA fragments and that of the drugs. Additionally, the changes to the bleomycin structure correlate with the changes to the DNA structure.