Sequence Selective Cleavage of a DNA Octanucleotide by Chlorinated Bithiazoles and Bleomycins

• Published in: Journal of the American Chemical Society Vol. 120; no. 36; pp. 9368 - 9369
• Main Authors: Zuber, G, Quada, JC Jr, Hecht, S M
• Format: Journal Article
• Language: English
• Published: 01.09.1998
• Subjects: bleomycin
• ISSN: 0002-7863
• DOI: 10.1021/ja981937r

The bleomycins (BLM) are a family of clinically used antitumor antibiotics. Their mechanism of action is believed to involve the degradation of DNA and possibly of RNA. BLM-mediated degradation requires a redox-active metal ion as well as oxygen and involves the intermediacy of a metal-bound oxo or peroxy species. The selectivity of DNA and RNA cleavage must reflect initial site-selective substrate binding, followed by oxidative degradation at sites that are sterically accessible following binding. While the bithiazole moiety clearly contributes to the DNA and RNA affinity of the BLMs, there is compelling evidence that the metal binding domain is responsible for the observed sequence selectivity of cleavage. Recently, attention has focused on the mode of DNA binding by metallobleomycins. Approaches have included DNA foot-printing and NMR spectroscopy, the latter of which has been combined with molecular dynamics calculations to provide models of Zn and Co times BLMs bound to DNA oligonucleotide substrates. The models are in agreement that the metal binding domain is oriented in the minor groove. In fact, the products of BLM-mediated DNA degradation must form by initial H atom abstraction from C4'H of deoxyribose, which resides in the minor groove of DNA. Many studies have attempted to define the mode(s) of DNA binding by the bithiazole moiety of BLM, but these fail to lead uniquely to a single type of interaction. Good evidence exists for groove binding, intercalation and partial intercalation in specific cases; this may reflect actual variations in the mode of binding from one system to another. The uncertainty concerning the nature of DNA binding by the bithiazole reflects the lack of any DNA structure modification mediated by this part of the BLM molecule.