A new family of rigid C2-symmetric cleft molecules as potential medicinal chemistry scaffolds

Abstract

The discovery of new scaffolds that selectively interact with biomolecules (e.g. DNA) supports the development of new medicinal and chemical biology tools, such as novel therapeutics and sensors. Whilst their binding and specificity is dependent on several well established factors, there has been an increasing emphasis on identifying scaffolds that possess intrinisic 3-dimensionality. Herein, we report the synthesis, photophysical and preliminary ds-DNA binding properties of a novel series C2-symmetric carbocyclic cleft scaffolds. The synthesis of two cleft ligands has been realised through a 4-step procedure with the structures of each molecule established through single crystal X-ray crystallography. The unique 3-dimension shape of these cleft molecules has allowed for accurate positioning of extended aromatic groups, which assist in their interaction with ds-DNA. This interaction was probed through UV-Vis titration studies of the racemic ligands with ct-DNA and the preliminary studies establish that the mode-of-binding with ct-DNA is via intercalation, which is further supported using computational DNA-docking studies.