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

The discovery of new scaffolds that selectively interact with biomolecules is vital in the development of new medicinal and chemical biology tools, therapeutics and sensors. Their binding and specificity is reliant on several well established factors, but 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 new series of 3-D C2-symmetric carbocyclic cleft scaffolds. Their synthesis is realised through a 4-step procedure with the structures of each molecule established through single crystal X-ray crystallography. Their interaction with ds-DNA is probed using UV-Vis titration of the racemic ligands with ct-DNA with the preliminary studies establishing that the mode-of-binding as intercalative, with Kb values between 1.28 x 106 to 2.32 x 105 M-1. This is further supported using computational DNA-docking studies that demonstrate that complementarity 3D shapes of these ligands is essential for B-DNA binding.