Small organic molecules with designed structures could specifically recognize DNA sequences. Such recognition offers a potential approach to the regulation of gene expression and the application for medical research. A barrier to progress in this area is the lack of a variety of modules that recognize single or multiple G●C base pairs (bp) in DNA sequences. To overcome this barrier, an entirely new design concept for modules that can bind to mixed AT and GC sequences of DNA is explored. Because of their successes in biological applications, minor-groove binding heterocyclic cations were selected as the platform for design. These type compounds are generally specific for A●T bp DNA sequences and expanded development requires recognition of G●C bp. Binding to AT sequences requires H-bond donors while recognition of the G-NH2 requires an acceptor. The concept described here uses preorganized thiophene-N-methylbenzimidazole (thiophene-N-MeBI) modules for selective binding with mixed bp DNA sequences. The interaction between the thiophene σ-hole (positive electrostatic potential) and electron donor nitrogen of N-MeBI preorganizes the conformation for accepting an H-bond from G-NH2. The rational combination of two σ-hole modules with a -O-(CH2)3-O- linker helps the compounds have the flexibility and appropriate length to match the curvature of two-G DNA sequences minor groove and cover a full turn of DNA helix. The compound-DNA interactions were evaluated with a powerful array of biophysical methods, and the results show that compounds with thiophene-N-MeBI modules can specifically recognize mixed DNA sequences with high affinity. In order to improve the binding selectivity and avoid AT binding ability, different sizes of alkyl groups are chosen to replace the methyl group of N-MeBI unite. Moreover, the alkyl groups indeed keep the strong target sequence binding affinity and decrease the binding with AT or other control sequences. These results show that the use of molecular features, such as thiophene-N-MeBI σ-hole module, can lead to new approaches for small molecules in biomolecular interactions.

Thiophene-N-methylbenzimidazole σ–hole module as a new road to specific recognition of mixed DNA sequences

255th National Meeting (2018)

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