Carbon-Hydrogen Bonds of DNA Sugar Units as Targets for Chemical Nucleases and Drugs

摘要

This review article focuses on the molecular aspects of DNA cleavage by synthetic chemical nucleases (transition metal complexes endowed with redox properties and DNA affinity) and natural drugs (cytotoxic agents such as bleomycins or enediynes). Unlike de-oxyribonucleases, which catalyze the nucleophilic attack of water on the phosphorus atom of a particular phos-phodiester entity, these nonhydrolytic DNA-cleavers are able to oxidize the sugar units, generally by hydrogen atom abstraction. Examplesof oxidative attack on each of the five different C-H bonds of deoxyribose are known, depending on the nature, structure, type of activation, or mode of DNA interaction of the DNA-cleaver. Further evolution at the site of the initial lesion leads to therelease of bases, oxidized deoxyribose units, or oxidized sugar fragments appended to the base or the terminal phosphate. In most cases the loss of a part (at least) of a nucleoside. with the concomitant loss of one base information, primarily induces the cleavage of the DNA strand. For both types of DNA cleavage reagents studied within the two last decades, the modes of activation and DNA binding are presented, as well as the details on the mechanism of deoxyribose oxidative degration. Because of the need for highly efficient and highly specific reagents, the development of new artificial and selective DNA cleavers, supported by an improved knowledge of these different mechanisms of DNA cleavage, is to-day a challenging area in the rational design ofanlitumoral or antiviral agents, as well as in the field of molecular biology.