The Thiophene "Sigma-Hole" as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove.

In spite of its importance in cell function, targeting DNA is under-represented in the design of small molecules. A barrier to progress in this area is the lack of a variety of modules that recognize G⋅C base pairs (bp) in DNA sequences. To overcome this barrier, an entirely new design concept for modules that can bind to mixed G⋅C and A⋅T sequences of DNA is reported herein. Because of their successes in biological applications, minor-groove-binding heterocyclic cations were selected as the platform for design. Binding to A⋅T sequences requires hydrogen-bond donors whereas recognition of the G-NH requires an acceptor. The concept that we report herein uses pre-organized N-methylbenzimidazole (N-MeBI) thiophene modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene sigma hole (positive electrostatic potential) and the electron-donor nitrogen of N-MeBI preorganizes the conformation for accepting an hydrogen bond from G-NH . The compound-DNA interactions were evaluated with a powerful array of biophysical methods and the results show that N-MeBI-thiophene monomer compounds can strongly and selectively recognize single G⋅C bp sequences. Replacing the thiophene with other moieties significantly reduces binding affinity and specificity, as predicted by the design concept. These results show that the use of molecular features, such as sigma-holes, can lead to new approaches for small molecules in biomolecular interactions.