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The Thiophene “Sigma‐Hole” as a Concept for Preorganized, Specific Recognition of G⋅C Base Pairs in the DNA Minor Groove
Author(s) -
Guo Pu,
Paul Ananya,
Kumar Arvind,
Farahat Abdelbasset A.,
Kumar Dhiraj,
Wang Siming,
Boykin David W.,
Wilson W. David
Publication year - 2016
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201603422
Subject(s) - thiophene , dna , base pair , hydrogen bond , small molecule , chemistry , molecule , stereochemistry , molecular recognition , groove (engineering) , biochemistry , materials science , organic chemistry , metallurgy
Abstract 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 2 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 2 . 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.