Camptothecin: Roles of the D and E Rings in Binding to the Topoisomerase I-DNA Covalent Binary Complex

The alkaloid camptothecin is the prototypical DNA topoisomerase I poison. This core structure has formed the basis for two marketed antitumor agents and numerous clinical candidates, and has been the focus of many synthetic and medicinal chemistry studies. Recent reports have furthered our understanding of the roles played by the D and E rings of camptothecin in stabilization of the enzyme-DNA-camptothecin ternary complex. Important parameters for further study and optimization include the facility of E-ring lactone hydrolysis and the prospects for replacing the E ring with more stable structures, the role of the 14-CH group in binary complex binding, and the effect of ternary complex dynamics on the expression of cytotoxicity by the camptothecins.