Assessment of atypical DNA intercalating agents in biological and in silico systems.
Non-covalent genotoxic interaction between DNA and classical planar fused-ring intercalating agents, has been well understood for some time especially in the context of frameshift mutagenesis in bacterial systems. Recent evidence, however, suggests that a rather wide structural range of small non-fused ring molecules may also be capable of partial or complete DNA intercalation in mammalian cells. The present paper will review recent studies on the identification and characterization of such atypically-structured molecules utilizing both cell-based and three-dimensional computational analyses focusing principally on prediction and detection of these atypical molecules. Mechanistic aspects of genotoxicity of such non-covalent binding molecules, with emphasis on marketed pharmaceuticals, will also be discussed. A review and presentation of new data using catalytic DNA topo II inhibitors, confirms the notion that topoisomerase II poisoning arising via intercalation is the major mechanism of genotoxicity of these drugs.
Snyder
Ronald D
RD
Department of Genetic and Molecular Toxicology, Schering-Plough Research Institute, 556 Morris Ave, Summit, NJ 07901, United States. Ronald.snyder@spcorp.com
D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D006224:Cricetinae; D003412:Cricetulus; D004247:DNA / Q000737:chemistry* / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D007364:Intercalating Agents / Q000737:chemistry* / Q000494:pharmacology*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D055672:Static Electricity; D059005:Topoisomerase II Inhibitors
D004791:Enzyme Inhibitors; D007364:Intercalating Agents; D008024:Ligands; D059005:Topoisomerase II Inhibitors; D004247:DNA