Playing Around with the Size and Shape of Quinolizinium ­Derivatives: Versatile Ligands for Duplex, Triplex, Quadruplex and Abasic Site-Containing DNA

Abstract

The association of heteroaromatic ligands with DNA is an important and biologically relevant process, because it may have a strong influence on the function of the nucleic acid. As a result, efficient and selective DNA-targeting ligands are considered as promising lead structures for drugs. In this context, we established the quinolizinium ion as a versatile building block for the design of DNA-binding ligands, with the long-term goal to evaluate and understand the structural parameters that govern the association of cationic hetarenes with DNA. In this account we demonstrate that annelated quinolizinium derivatives are easily available and that their structure and substitution pattern are highly variable. Most notably, the availability of several derivatives with different size and shape enables the assessment of structure–property relationships regarding their DNA-binding properties. It is shown with exemplary case studies that the systematic variation of the ligand structure, along with analysis of the binding parameters, can be employed to analyze the structural requirements of a ligand to bind to different DNA forms, such as triplex, quadruplex and abasic site-containing DNA. 1 Introduction 2 Association of Quinolizinium Derivatives with Double-Stranded DNA 3 Association of Quinolizinium Derivatives with Triplex DNA 4 Association of Quinolizinium Derivatives with Quadruplex DNA 5 Association of Quinolizinium Derivatives with Abasic Positions in DNA 6 Conclusion